Inhibitors of factor Xa

ABSTRACT

Novel compounds, their salts and compositions related thereto having activity against mammalian factor Xa are disclosed. The compounds of formula (I) below:                    
     are useful in vitro or in vivo for preventing or treating coagulation disorders.

RELATED APPLICATIONS

This application claims benefit of priority under 35 USC § 119(e) toU.S. Provisional Application No. 60/202,202 filed on May 5, 2000 andU.S. Provisional Application No. 60/148,627 filed on Aug. 12, 1999,which are both herein incorporated in their entirety by reference.

FIELD OF THE INVENTION

This invention relates to novel compounds which are potent and highlyselective inhibitors of isolated factor Xa or factor Xa when assembledin the prothrombinase complex. These compounds show selectivity forfactor Xa versus other proteases of the coagulation (e.g. thrombin,fVIIa, fIXa) or the fibrinolytic cascades (e.g. plasminogen activators,plasmin). In another aspect, the present invention relates to novelmonoamidino-containing compounds, their pharmaceutically acceptablesalts, and pharmaceutically acceptable compositions thereof which areuseful as potent and specific inhibitors of blood coagulation inmammals. In yet another aspect, the invention relates to methods forusing these inhibitors as therapeutic agents for disease states inmammals characterized by coagulation disorders.

BACKGROUND OF THE INVENTION

Hemostasis, the control of bleeding, occurs by surgical means, or by thephysiological properties of vasoconstriction and coagulation. Thisinvention is particularly concerned with blood coagulation and ways inwhich it assists in maintaining the integrity of mammalian circulationafter injury, inflammation, disease, congenital defect, dysfunction orother disruption. Although platelets and blood coagulation are bothinvolved in thrombus formation, certain components of the coagulationcascade are primarily responsible for the amplification or accelerationof the processes involved in platelet aggregation and fibrin deposition.

Thrombin is a key enzyme in the coagulation cascade as well as inhemostasis. Thrombin plays a central role in thrombosis through itsability to catalyze the conversion of fibrinogen into fibrin and throughits potent platelet activation activity. Direct or indirect inhibitionof thrombin activity has been the focus of a variety of recentanticoagulant strategies as reviewed by Claeson, G., “Synthetic Peptidesand Peptidomimetics as Substrates and Inhibitors of Thrombin and OtherProteases in the Blood Coagulation System”, Blood Coag. Fibrinol. 5,411-436 (1994). Several classes of anticoagulants currently used in theclinic directly or indirectly affect thrombin (i.e. heparins,low-molecular weight heparins, heparin-like compounds and coumarins).

A prothrombinase complex, including Factor Xa (a serine protease, theactivated form of its Factor X precursor and a member of the calcium ionbinding, gamma carboxyglutamyl (Gla)-containing, vitamin K dependent,blood coagulation glycoprotein family), converts the zymogen prothrombininto the active procoagulant thrombin. Unlike thrombin, which acts on avariety of protein substrates as well as at a specific receptor, factorXa appears to have a single physiologic substrate, namely prothrombin.Since one molecule of factor Xa may be able to generate up to 138molecules of thrombin (Elodi et al., Thromb. Res. 15, 617-619 (1979)),direct inhibition of factor Xa as a way of indirectly inhibiting theformation of thrombin may be an efficient anticoagulant strategy.Therefore, it has been suggested that compounds which selectivelyinhibit factor Xa may be useful as in vitro diagnostic agents, or fortherapeutic administration in certain thrombotic disorders, see e.g., WO94/13693.

Polypeptides derived from hematophagous organisms have been reportedwhich are highly potent and specific inhibitors of factor Xa. U.S. Pat.No. 4,588,587 describes anticoagulant activity in the saliva of theMexican leech, Haementeria officinalis. A principal component of thissaliva was shown to be the polypeptide factor Xa inhibitor, antistasin(ATS), by Nutt, E. et al., “The Amino Acid Sequence of Antistasin, aPotent Inhibitor of Factor Xa Reveals a Repeated Internal Structure”, J.Biol. Chem., 263, 10162-10167 (1988). Another potent and highly specificinhibitor of Factor Xa, called tick anticoagulant peptide (TAP), hasbeen isolated from the whole body extract of the soft tick Omnithidorosmoubata, as reported by Waxman, L., et al., “Tick Anticoagulant Peptide(TAP) is a Novel Inhibitor of Blood Coagulation Factor Xa” Science, 248593-596 (1990).

Factor Xa inhibitory compounds which are not large polypeptide-typeinhibitors have also been reported including: Tidwell, R. R. et al.,“Strategies for Anticoagulation With Synthetic Protease Inhibitors. XaInhibitors Versus Thrombin Inhibitors”, Thromb. Res., 19, 339-349(1980); Turner, A. D. et al., “p-Amidino Esters as IrreversibleInhibitors of Factor IXa and Xa and Thrombin”, Biochemistry, 25,4929-4935 (1986); Hitomi, Y. et al., “Inhibitory Effect of New SyntheticProtease Inhibitor (FUT-175) on the Coagulation System”, Haemostasis,15, 164-168 (1985); Sturzebecher, J. et al., “Synthetic Inhibitors ofBovine Factor Xa and Thrombin. Comparison of Their AnticoagulantEfficiency”, Thromb. Res., 54, 245-252 (1989); Kam, C. M. et al.,“Mechanism Based Isocoumarin Inhibitors for Trypsin and BloodCoagulation Serine Proteases: New Anticoagulants”, Biochemistry, 27,2547-2557 (1988); Hauptmann, J. et al., “Comparison of the Anticoagulantand Antithrombotic Effects of Synthetic Thrombin and Factor XaInhibitors”, Thromb. Haemost., 63, 220-223 (1990); and the like.

Others have reported Factor Xa inhibitors which are small moleculeorganic compounds, such as nitrogen containing heterocyclic compoundswhich have amidino substituent groups, wherein two functional groups ofthe compounds can bind to Factor Xa at two of its active sites. Forexample, WO 98/28269 describes pyrazole compounds having a terminalC(═NH)—NH₂ group; WO 97/21437 describes benzimidazole compoundssubstituted by a basic radical which are connected to a naththyl groupvia a straight or branched chain alkylene, —C(═O) or —S(═O)₂ bridginggroup; WO 99/10316 describes compounds having a4-phenyl-N-alkylamidino-piperidine and4-phenoxy-N-alkylarnidino-piperidine group connected to a3-amidinophenyl group via a carboxamidealkyleneamino bridge; and EP798295 describes compounds having a 4-phenoxy-N-alkylamidino-piperidinegroup connected to an amidinonaphthyl group via a substituted orunsubstituted sulfonamide or carboxamide bridging group.

There exists a need for effective therapeutic agents for the regulationof hemostasis, and for the prevention and treatment of thrombusformation and other pathological processes in the vasculature induced bythrombin such as restenosis and inflammation. In particular, therecontinues to be a need for compounds which selectively inhibit factor Xaor its precursors. Compounds that have different combinations ofbridging groups and functional groups than compounds previouslydiscovered are needed, particularly compounds which selectively orpreferentially bind to Factor Xa. Compounds with a higher degree ofbinding to Factor Xa than to thrombin are desired, especially thosecompounds having good bioavailability and/or solubility.

SUMMARY OF THE INVENTION

The present invention relates to novel compounds which inhibit factorXa, their pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives, and pharmaceutically acceptable compositionsthereof which have particular biological properties and are useful aspotent and specific inhibitors of blood coagulation in mammals.Pharmaceutical compositions of the invention may be used to prevent ortreat a condition in a mammal characterized by undesired thrombosis. Inanother aspect, the invention relates to methods of using theseinhibitors as diagnostic reagents or as therapeutic agents for diseasestates in mammals which have coagulation disorders, such as in thetreatment or prevention of a condition in a mammal characterized byundesired thrombosis such as, for example, any thrombotically mediatedacute coronary or cerebrovascular syndrome, any thrombotic syndromeoccurring in the venous system, any coagulopathy, and any thromboticcomplications associated with extracorporeal circulation orinstrumentation, and for the inhibition of coagulation of biologicalsamples and blood in biological samples.

In certain embodiments, this invention relates to novel compounds whichare potent and highly selective inhibitors of isolated factor Xa orfactor Xa when assembled in the prothrombinase complex. These compoundsshow selectivity for factor Xa versus other proteases of the coagulationcascade (e.g. thrombin, etc.) or the fibrinolytic cascade, and areuseful as diagnostic reagents as well as antithrombotic agents.

In a preferred embodiment, the present invention provides a compound ofthe formula I:

wherein:

A is selected from:

(a) C₁-C₆-alkyl;

(b) C₃-C₈-cycloalkyl;

(c) —N(—R²,—R³), R³—C(═N—R²)—, (—R², —R³)N—C(═N—R²)—, (—R²,—R³)N—C(═N—R²)—N(—R—)—

(d) phenyl, which is independently substituted with 0-2 R¹ substituents;

(e) naphthyl, which is independently substituted with 0-2 R¹substituents; and

(f) a monocyclic or fused bicyclic heterocyclic ring system having from5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system areselected from N, O and S, and wherein the ring system may be substitutedwith 0-2 R¹ substituents;

R¹ is selected from:

Halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈scycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, R²—C(═N—R³)—, (—R², —R³)N—C(═N—R²)—,(—CH₂)_(m)NR²R³, —C(═O)—N(—R², —R³), —SO₂N(—R², —R³), —SO₂R², —CF₃,—OR², and a 5-6 membered aromatic heterocyclic system containing from1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogenatoms on the aromatic heterocyclic system may be independently replacedwith a member selected from the group consisting of halo, C₁-C₄-alkyl,—CN C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkenyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;

R² and R³ are independently selected from the group consisting of:

H, —OR², —N(—R², —R³), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and—C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms ofthe phenyl and naphthyl moieties may be independently replaced with amember selected from the group consisting of halo, —C₁₋₄alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,—CN, and —NO₂;

or R² and R³ taken together can form a 3-8 membered cycloalkyl or aheterocyclic ring system, wherein the heterocyclic ring system may havefrom 5 to 10 ring atoms, with 1 to 2 rings being in the ring system andcontain from 1-4 heteroatoms selected from N, O and S, wherein from 1-4hydrogen atoms on the heterocyclic ring system may be independentlyreplaced with a member selected from the group consisting of halo,C₁-C₄-alkyl, —CN —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;

m is an integer of 0-2;

Q is a member selected from the group consisting of:

a direct link, —CH2—, —C(═O)—, —N(R⁴)—, —N(R⁴)CH2—, —C═N(R4)—,—C(═O)—N(R⁴)—, —N(R⁴)—C(═O)—, —SO₂—, —O—, —SO₂—N(R⁴)— and —N(R⁴)—SO₂—;

R⁴ is selected from:

H, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and —C₀₋₄alkylnaphthyl,wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl andnaphthyl moieties may be independently replaced with a member selectedfrom the group consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;

D is a member selected from the group consisting of:

(a) phenyl, which is independently substituted with 0-2 R^(1a)substituents; and

(b) an aromatic six-membered heterocyclic ring having from 1-2 ringnitrogen atoms, and wherein the ring atoms may be substituted with 0-2R^(1a) substituents;

R^(1a) is selected from:

Halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, (CH₂)_(m)NR^(2a)R^(3a),SO₂NR^(2a)R^(3a), SO₂R^(2a), CF₃, OR^(2a), and a 5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from N, Oand S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclicsystem may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;

R^(2a) and R^(3a) are independently selected from the group consistingof:

C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;

M is a member selected from the group consisting of:

—N(R¹⁶)—C(═O)—, —N(R¹⁶)—C(═S)—, —C(—R¹⁷,—R¹⁸)—C(═O)—,—C(—R¹⁷,—R¹⁸)—C(═S)—, —C(—R¹⁷,R^(17a))—C(—R¹⁸,—R^(18a))—,—C(—R¹⁹,—R^(19a))—C(—R¹⁷,—R^(17a))—C(—R¹⁸,—R^(18a))—,—C(—R¹⁷)═C(—R¹⁸)—C(═O)—, —C(—R¹⁷)═C(—R¹⁸)—C(═S)—, —C(—R¹⁷)═C(—R¹⁸)—,—O—C(—R¹⁷,—R¹⁸)—C(═O)—, —O—C(—R¹⁷,—R¹⁸)—C(═S)—, —S—C(—R¹⁷,—R¹⁸)—C(═O)—,—S(═O)₂—C(—R¹⁷,—R¹⁸)—C(═O)—, —S(═O)—C(—R¹⁷,—R¹⁸)—C(═O)—,—S—C(—R¹⁷,—R¹⁸)—C(═S)—, —S(═O)₂—C(—R¹⁷,—R¹⁸)—C(═S)—,—S(═O)—C(—R¹⁷,—R¹⁸)—C(═S)—, —C(═O)—C(═O)—, —N(R¹⁶)—C(—R¹⁷,—R¹⁸)—C(═O)—,—N(R¹⁶)—C(—R¹⁷,—R¹⁸)—C(═S)—, —C(═S)—C(═S)—, —C(═S)—C(═O)—,—C(═O)—C(═S)—, —N═C(—R¹⁷)—C(═O)—, —N═C(—R¹⁷)—C(═S)—, —C(—R¹⁷)═N—,—N(—R¹⁶)—C(═O)—C(—R¹⁸,—R^(18a))—C(—R¹⁷,—R^(17a))—,—O—C(—R¹⁸,—R^(18a))—C(—R¹⁷,—R^(17a))—,—N(—R¹⁶)—C(═S)—C(—R¹⁸,—R^(18a))—C(—R¹⁷,—R^(17a))—,—S(═O)—C(—R¹⁸,—R^(18a))—C(—R¹⁷,—R^(17a))—,—S(═O)₂—C(—R¹⁸,—R^(18a))—C(—R¹⁷,—R^(17a))—,—C(═C(R^(17b),—R^(17c)))—C(═O)—, —C(═C(R^(17b),—R^(17c)))—C(═S)—,—N(—R¹⁶)—C(—R¹⁸,—R^(18a))—C(—R¹⁷,—R^(17a))—C(═S)—,—N(—R¹⁶)—C(—R¹⁸,—R^(18a))—C(—(N(—H,—R^(18b))),—R^(17a))—C(═O)—;—N═C(—R¹⁷)— and —N(—R¹⁶)—C(—R¹⁸,—R^(18a))—C(—(N(—H,—R^(18b))),—R^(17a))—C(═S)—; wherein the first named atom of the chain is directlyattached to D, and wherein D, M and the N atom attached to the lastchain atom of M collectively form a bicyclic ring structure;

R¹⁶, R¹⁷, R^(17a), R¹⁸, R^(18a), R^(18b), R¹⁹, and R^(19a) are eachindependently selected from the consisting of:

hydrogen, halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, (CH₂)_(m)NR²R³, SO₂NR²R³, SO₂R²,CF₃, OR², and a 5-6 membered aromatic heterocyclic system containingfrom 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogenatoms on the aromatic heterocyclic system may be independently replacedwith a member selected from the group consisting of halo, C₁-C₄-alkyl,—CN, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;

R^(17b) and R^(17c) are each independently a member selected from thegroup consisting of

hydrogen, -halo, hydroxy, —C₁₋₄alkyl, C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₄alkyl-C₃₋₈cycloalkyl, —CN, —NO₂, —(CH₂)_(m)NR²R³,—SO₂NR²R³, —SO₂R², —CF₃, —OR², phenyl, and a 5-6 membered aromaticheterocyclic ring containing from 1-4 heteroatoms selected from N, O andS, wherein from 1-4 hydrogen atoms on the cycloalkyl, the phenyl ring,or the aromatic heterocyclic ring may be independently replaced with amember selected from the group consisting of halo, C₁-C₄-alkyl, —CN,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;

E is a member selected from the group consisting of:

a direct link, —C(═O)—, —C(═O)—N(R⁵)—, —C(—R^(5a),—R^(6a))— and—C(—R^(5b),—R^(6b))—C(—R^(5c),—R^(6c))—;

wherein R⁵, R^(5a), R^(6a), R^(5b), R^(6b), R^(5c) and R^(6c) areindependently selected from:

H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl,C₀₋₄alkylheteroaryl, C₁₋₄alkylCOOH and C₁₋₄alkylCOOC₁₋₄alkyl, whereinfrom 0-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl andheteroaryl moieties may be independently replaced with a member selectedfrom the group consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —OH, —O—C₁₋₄alkyl, —SH,—S—C₁₋₄alkyl, —CN and —NO₂;

G is selected from:

a direct link, —C(R⁷,R⁸)—, —C(R^(7a),R^(8a))—C(R^(7b),R^(8b))— and—C(R^(7c))═C(R^(8c))—;

wherein R⁷, R⁸, R^(7a), R^(8a), R^(7b), R^(8b), R^(7c) and R^(8c) areindependently a member selected from from the group consisting of:

hydrogen, halogen, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkyl-C₃₋₈cycloalkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, —OR⁹,—N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹, —C₀₋₄alkylC(═O)NR⁹R¹⁰, —C₀₋₄alkyIC(═O)OR⁹,—C₀₋₄alkylC(═O)NR⁹—CH₂—CH₂—O—R¹⁰, —C₀₋₄alkylC(═O)NR⁹(—CH₂—CH₂—O—R¹⁰—)₂,—N(R⁹)COR¹⁰, —N(R⁹)C(═O)R¹⁰,—N(R⁹)SO₂R¹⁰, a naturally occurring orsynthetic amino acid side chain, and C₀₋₄alkylheterocyclic ring havingfrom 1 to 4 hetero ring atoms selected from the group consisting of N, Oand S, CH₂COOC₁₋₄alkyl, CH₂COOC₁₋₄alkylphenyl andCH₂COOC₁₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on theC₀₋₄alkylheterocyclic ring may be independently replaced with a memberselected from the group consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;

wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl andnaphthyl moieties may be independently replaced with a member selectedfrom the group consisting of halo, —OR⁹, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkyl-C₃₋₈cycloalkyl, —CN and —NO₂;

R⁹ and R¹⁰ are independently selected from:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, C₃₋₈cycloalkyl, andC₁₋₄alkyl-O—C₁₋₄alkyl, C₁₋₄alkyl-COOH wherein from 1-4 hydrogen atoms onthe ring atoms of the phenyl and naphthyl moieties may be independentlyreplaced with a member selected from the group consisting of halo,C₁₋₄alkyl, C₂₋₆alkenyl, C₂6alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkyl-C₃₋₈cycloalkyl, —CN and —NO₂, and wherein R⁹ and R¹⁰ takentogether can form a 5-8 membered heterocylic ring;

J is a member selected from the group consisting of:

a direct link, —O—, —O—C(—R¹¹, —R^(11a))—, —S—, —S(═O)—,—S(═O) ₂—,—S—C(—R¹¹, —R^(11a))—, —S(═O)—C(—R¹¹, —R^(11a))—, —S(═O)₂—(—R¹¹,—R^(11a))—, —C(═O)—, —C(═O)—N(R^(11b))—, —N(R^(11b))—C(═O)—,—N(R^(11b))—, —N(R^(11b))—C(—R¹¹, —R^(11a))— and a monocyclic aromaticor non-aromatic heterocyclic ring having from 5 to 8 ring atoms, wherein1-4 ring atoms of the ring system are selected from N, O and S, andwherein the ring system may be substituted with 0-2 R¹¹ substituents;

R¹¹, R^(11a), R^(11b), and R¹¹ are a member independently selected fromthe group consisting of:

hydrogen, halo, —CF₃, —CN, —NR⁹R¹⁰, —SO₂Me, —NO₂, —OH, —O—C₁₋₄alkyl,—O—C₂₋₆alkenyl, —O—C₂₋₆alkynyl, —O—C₃₋₈cycloalkyl,—O—C₁₋₄alkyl-O—C₁₋₄alkyl, —O—C₁₋₄alkyl-COOH, —O—C₁₋₄alkyl-phenyl, —COOH,—C(═O)—O—C₁₋₄alkyl, —C(═O)—O—C₂₋₆alkenyl, —C(═O)—O—C₂₋₆alkynyl,—C(═O)—O—C₃₋₈cycloalkyl, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkyl-C₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, C₀₋₄alkylC(═O)NR⁹R¹⁰, C₀₋₄alkylC(═O)OR⁹,C₀₋₄alkylheterocyclic ring having from 1 to 4 hetero ring atoms selectedfrom the group consisting of N, O and S, CH₂COOC₁₋₄alkyl,CH₂COOC₁₋₄alkylphenyl and CH₂COOC₁₋₄alkylnaphthyl; wherein from 1-4hydrogen atoms on the C₀₋₄alkylheterocyclic ring may be independentlyreplaced with a member selected from the group consisting of halo,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkyl-phenyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;

wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl andnaphthyl moieties may be independently replaced with a member selectedfrom the group consisting of halo, —OR⁹, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkyl-C₃₋₈cycloalkyl, —CN and —NO₂;

Y is a member selected from the group consisting of:

(a) phenyl, which is independently substituted with 0-2 R^(1b)substituents;

(b) naphthyl, which is independently substituted with 0-2 R^(1b)substituents; and

(c) a monocyclic or fused bicyclic heterocyclic ring system having from5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system areselected from N, O and S, and wherein the ring system may be substitutedwith 0-2 R^(1b) substituents;

R^(1b) is a member selected from the group consisting of:

halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloaklyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, NR^(2b)R^(3b), SO₂NR^(2b)R^(3b),SO₂R^(2b), CF₃, OR^(2b), O—CH₂—CH₂—OR^(2b), O—CH₂-COOR^(2b),N(^(2b))—CH₂—CH₂—OR^(2b), N(—CH₂—CH₂—OR^(2b))₂, N(R^(2b))—C(═O)R^(3b),N(R^(2b))—SO₂—R^(3b), and a 5-6 membered aromatic heterocyclic systemcontaining from 1-4 heteroatoms selected from N, O and S, wherein from1-4 hydrogen atoms on the aromatic heterocyclic system may beindependently replaced with a member selected from the group consistingof halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkyl-phenyl, —CN and —NO₂;

R^(2b) and R^(3b) are independently selected from the group consistingof:

H, C₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloaklyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, —OR⁹, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycoalkyl, —CN and —NO₂;

L is selected from:

H, —CN, C(═O)NR¹²R¹³, —(CH₂)_(n)NR¹²R¹³, C(═NR¹²)NR¹²R¹³, OR¹²,—NR¹²C(═NR¹²)NR¹²R¹³, and NR¹²C(═NR¹²)—R¹³;

n is an integer from 0 to 8;

R¹² and R¹³ are independently selected from:

hydrogen, —OR¹⁴, —NR¹⁴R¹⁵, C₁₋₄alkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, COOC₁₋₄alkyl, COO—C₀₋₄alkylphenyl andCOO—C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atomsof the phenyl and naphthyl moieties may be independently replaced with amember selected from the group consisting of halo, —OH, —O—C₁₋₄alkyl,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;

R¹⁴ and R¹⁵ are independently selected from:

H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In certain aspects of this invention, compounds are provided which areuseful as diagnostic reagents. In another aspect, the present inventionincludes pharmaceutical compositions comprising a pharmaceuticallyeffective amount of the compounds of this invention and apharmaceutically acceptable carrier. In yet another aspect, the presentinvention includes methods comprising using the above compounds andpharmaceutical compositions for preventing or treating disease statescharacterized by disorders of the blood coagulation process in mammals,or for preventing coagulation in stored blood products and samples.Optionally, the methods of this invention comprise administering thepharmaceutical composition in combination with an additional therapeuticagent such as an antithrombotic and/or a thrombolytic agent and/or ananticoagulant.

The preferred compounds also include their pharmaceutically acceptableisomers, hydrates, solvates, salts and prodrug derivatives.

DETAILED DESCRIPTION OF THE INVENTION Definitions

In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The term “alkenyl” refers to a trivalent straight chain or branchedchain unsaturated aliphatic radical. The term “alkinyl” (or “alkynyl”)refers to a straight or branched chain aliphatic radical that includesat least two carbons joined by a triple bond. If no number of carbons isspecified alkenyl and alkinyl each refer to radicals having from 2-12carbon atoms.

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain and cyclic groups having the number ofcarbon atoms specified, or if no number is specified, having up to 12carbon atoms. The term “cycloalkyr” as used herein refers to a mono-,bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms andpreferably 3 to 7 carbon atoms.

As used herein, the terms “carbocyclic ring structure” and“C₃₋₁₆carbocyclic mono, bicyclic or tricyclic ring structure” or thelike are each intended to mean stable ring structures having only carbonatoms as ring atoms wherein the ring structure is a substituted orunsubstituted member selected from the group consisting of: a stablemonocyclic ring which is aromatic ring (“aryl”) having six ring atoms; astable monocyclic non-aromatic ring having from 3 to 7 ring atoms in thering; a stable bicyclic ring structure having a total of from 7 to 12ring atoms in the two rings wherein the bicyclic ring structure isselected from the group consisting of ring structures in which both ofthe rings are aromatic, ring structures in which one of the rings isaromatic and ring structures in which both of the rings arenon-aromatic; and a stable tricyclic ring structure having a total offrom 10 to 16 atoms in the three rings wherein the tricyclic ringstructure is selected from the group consisting of: ring structures inwhich three of the rings are aromatic, ring structures in which two ofthe rings are aromatic and ring structures in which three of the ringsare non-aromatic. In each case, the non-aromatic rings when present inthe monocyclic, bicyclic or tricyclic ring structure may independentlybe saturated, partially saturated or fully saturated. Examples of suchcarbocyclic ring structures include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, cyclooctyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), 2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl (tetralin). Moreover, the ringstructures described herein may be attached to one or more indicatedpendant groups via any carbon atom which results in a stable structure.The term “substituted” as used in conjunction with carbocyclic ringstructures means that hydrogen atoms attached to the ring carbon atomsof ring structures described herein may be substituted by one or more ofthe substituents indicated for that structure if such substitution(s)would result in a stable compound.

The term “aryl” which is included with the term “carbocyclic ringstructure” refers to an unsubstituted or substituted aromatic ring,substituted with one, two or three substituents selected fromloweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano,hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl,carboalkoxy and carboxamide, including but not limited to carbocyclicaryl, heterocyclic aryl, and biaryl groups and the like, all of whichmay be optionally substituted. Preferred aryl groups include phenyl,halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl andnaphthacenyl.

The term “arylalkyl” which is included with the term “carbocyclic aryl”refers to one, two, or three aryl groups having the number of carbonatoms designated, appended to an alkyl group having the number of carbonatoms designated. Suitable arylalkyl groups include, but are not limitedto, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, andthe like, all of which may be optionally substituted.

As used herein, the term “heterocyclic ring” or “heterocyclic ringsystem” is intended to mean a substituted or unsubstituted memberselected from the group consisting of stable monocyclic ring having from5-7 members in the ring itself and having from 1 to 4 hetero ring atomsselected from the group consisting of N, O and S; a stable bicyclic ringstructure having a total of from 7 to 12 atoms in the two rings whereinat least one of the two rings has from 1 to 4 hetero atoms selected fromN, O and S, including bicyclic ring structures wherein any of thedescribed stable monocyclic heterocyclic rings is fused to a hexane orbenzene ring; and a stable tricyclic heterocyclic ring structure havinga total of from 10 to 16 atoms in the three rings wherein at least oneof the three rings has from 1 to 4 hetero atoms selected from the groupconsisting of N, O and S. Any nitrogen and sulfur atoms present in aheterocyclic ring of such a heterocyclic ring structure may be oxidized.Unless indicated otherwise the terms “heterocyclic ring” or“heterocyclic ring system” include aromatic rings, as well asnon-aromatic rings which can be saturated, partially saturated or fullysaturated non-aromatic rings. Also, unless indicated otherwise the term“heterocyclic ring system” includes ring structures wherein all of therings contain at least one hetero atom as well as structures having lessthan all of the rings in the ring structure containing at least onehetero atom, for example bicyclic ring structures wherein one ring is abenzene ring and one of the rings has one or more hetero atoms areincluded within the term “heterocyclic ring systems” as well as bicyclicring structures wherein each of the two rings has at least one heteroatom. Moreover, the ring structures described herein may be attached toone or more indicated pendant groups via any hetero atom or carbon atomwhich results in a stable structure. Further, the term “substituted”means that one or more of the hydrogen atoms on the ring carbon atom(s)or nitrogen atom(s) of the each of the rings in the ring structuresdescribed herein may be replaced by one or more of the indicatedsubstituents if such replacement(s) would result in a stable compound.Nitrogen atoms in a ring structure may be quaternized, but suchcompounds are specifically indicated or are included within the term “apharmaceutically acceptable salt” for a particular compound. When thetotal number of O and S atoms in a single heterocyclic ring is greaterthan 1, it is preferred that such atoms not be adjacent to one another.Preferably, there are no more that I O or S ring atoms in the same ringof a given heterocyclic ring structure.

Examples of monocylic and bicyclic heterocylic ring systems, inalphabetical order, are acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structuresinclude, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl,1H-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring andspiro compounds containing, for example, the above heterocylic ringstructures.

As used herein the term “aromatic heterocyclic ring system” hasessentially the same definition as for the monocyclic and bicyclic ringsystems except that at least one ring of the ring system is an aromaticheterocyclic ring or the bicyclic ring has an aromatic or non-aromaticheterocyclic ring fused to an aromatic carbocyclic ring structure.

The terms “halo” or “halogen” as used herein refer to Cl, Br, F or Isubstituents. The term “haloalkyl”, and the like, refer to an aliphaticcarbon radicals having at least one hydrogen atom replaced by a Cl, Br,F or I atom, including mixtures of different halo atoms. Trihaloalkylincludes trifluoromethyl and the like as preferred radicals, forexample.

The term “methylene” refers to —CH₂—. The term “Bu” refers to “butyl” or—CH₂CH₂CH₂CH₂—; the term “Ph” refers to “phenyl”; the term “Me” refersto “methyl” or —CH₃; the term “Et” refers to “ethyl” or —CH₂CH₃; theterm “Bu(t)” or “t-Bu” refers to “tert-butyl” or —C(CH₃)₄.

The term “amino acid side chain” includes any naturally occurring orsynthetic side chain, i.e. the side chain “R” of an amino acid havingthe formula: NM₂—CHR—COOH. Synthetic amino acids include both (R) and(S) enantiomers, as well as derivatives of the naturally-occuring aminoacid side chains. The side chain may be any synthetic amino acid sidechain known in the art, including but not limited to, those produced byrecombinant DNA techniques, fermentation, or by solid phase synthesistechniques. Such synthetic amino acid side chains may contain one ormore functional groups selected from the following: alky, aryl, alkenyl,alkinyl, thiols, primary and secondary amines, aldehydes, carboxylates,nitrites, aromatic amines, aromatic carboxylates, primary alcohols, andthe like.

The term “pharmaceutically acceptable salts” includes salts of compoundsderived from the combination of a compound and an organic or inorganicacid. These compounds are useful in both free base and salt form. Inpractice, the use of the salt form amounts to use of the base form; bothacid and base addition salts are within the scope of the presentinvention.

“Pharmaceutically acceptable acid addition salt” refers to saltsretaining the biological effectiveness and properties of the free basesand which are not biologically or otherwise undesirable, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic nontoxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine.

“Biological property” for the purposes herein means an in vivo effectoror antigenic function or activity that is directly or indirectlyperformed by a compound of this invention that are often shown by invitro assays. Effector functions include receptor or ligand binding, anyenzyme activity or enzyme modulatory activity, any carrier bindingactivity, any hormonal activity, any activity in promoting or inhibitingadhesion of cells to an extracellular matrix or cell surface molecules,or any structural role. Antigenic functions include possession of anepitope or antigenic site that is capable of reacting with antibodiesraised against it.

In the compounds of this invention, carbon atoms bonded to fournon-identical substituents are asymmetric. Accordingly, the compoundsmay exist as diastereoisomers, enantiomers or mixtures thereof Thesyntheses described herein may employ racemates, enantiomers ordiastereomers as starting materials or intermediates. Diastereomericproducts resulting from such syntheses may be separated bychromatographic or crystallization methods, or by other methods known inthe art. Likewise, enantiomeric product mixtures may be separated usingthe same techniques or by other methods known in the art. Each of theasymmetric carbon atoms, when present in the compounds of thisinvention, may be in one of two configurations (R or S) and both arewithin the scope of the present invention.

Preferred Embodiments

In a preferred embodiment, the present invention provides a compoundaccording to the formula I:

wherein:

A is selected from:

(a) C₁-C₆-alkyl;

(b) C₃-C₈-cycloalkyl;

(c) phenyl, which is independently substituted with 0-2 R¹ substituents;

(d) naphthyl, which is independently substituted with 0-2 R¹substituents; and

(e) a monocyclic or fused bicyclic heterocyclic ring system having from5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system areselected from the group consisting of N, O and S, and wherein the ringsystem may be substituted with 0-2 R¹ substituents;

R¹ is selected from:

halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, —(CH₂)_(m)NR²R³, —SO₂NR²R³, —SO₂R²,—CF₃, —OR², and a 5-6 membered aromatic heterocyclic system containingfrom 1-4 heteroatoms selected from the group consisting of N, O and S,wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system maybe independently replaced with a member selected from the groupconsisting of halo, —C₁-C₄-alkyl, —CN, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;

R² and R³ are independently selected from the group consisting of:

H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;

m is an integer of 0-2;

Q is a member selected from the group consisting of:

a direct link, —C(═O)—, —N(R⁴)—, —C(═O)—N(R⁴)—, —N(R⁴)—C(═O)—, —SO₂—,—O—, —SO₂—N(R⁴)— and —N(R⁴)—SO₂—;

R⁴ is selected from:

H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alky1, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;

D is a member selected from the group consisting of:

(a) phenyl, which is independently substituted with 0-2 R^(1a)substituents; and

(b) an aromatic six-membered heterocyclic ring having from 1-2 ringnitrogen atoms, and wherein the ring atoms may be substituted with 0-2R^(1a) substituents;

R^(1a) is selected from:

halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, (CH₂)_(m)NR^(2a)R^(3a),SO₂NR^(2a)R^(3a), SO₂R^(2a), CF₃, OR^(2a), and a 5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from N, Oand S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclicsystem may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;

R^(2a) and R^(3a) are independently selected from the group consistingof:

H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;

M, D and N collectively form a bicyclic ring structure selected from thegroup consisting of:

 and the like, wherein the aromatic carbocyclic ring corresponding tothe D portion for each of the bicyclic rings may be replaced with anaromatic heterocylic ring as defined above for D, and wherein 0 to 2 ofthe hydrogen atoms on the D portion of the bicyclic ring may be replacedby R^(1a) substituents as defined above;

R¹⁶, R¹⁷, R^(17a), R¹⁸, R^(18a), R^(18b), R¹⁹ and R^(19a) are eachindependently selected form the group consisting of:

halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, (CH₂)_(m)NR²R³, SO₂NR²R³, SO₂R²,CF₃, OR², and a 5-6 membered aromatic heterocyclic system containingfrom 1-4 heteroatoms selected from N, O and S, wherein from 1-4 hydrogenatoms on the aromatic heterocyclic system may be independently replacedwith a member selected form the group consisting of halo, C₁-C₄-alkyl,—CN, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂;

R^(17b) and R^(17c) are each independently a member selected from thegroup consisting of:

hydrogen, -halo, hydroxy, —C₁₋₄alkyl, C₂₋₆alkenyl, —C₂₋₆alkynyl,—C₃₋₈cycloalkyl, —C₀₋₄alkyl-C₃₋₈cycloalkyl, —CN, —NO₂, —(CH₂)_(m)NR²R³,—SO₂NR²R³, —SO₂R², —CF₃, —OR², phenyl, and a 5-6 membered aromaticheterocyclic ring containing from 1-4 heteroatoms selected from N, O andS, wherein from 1-4 hydrogen atoms on the cycloalkyl, the phenyl ring,or the aromatic heterocyclic ring may be independently replaced with amember selected from the group consisting of halo, C₁-C₄-alkyl, —CN,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃-8cycloalkyl and —NO₂;

E is a member selected from the group consisting of:

a direct link, —C(═O)—, —C(═O)—N(R⁵)—, —C(—R^(5a), —R^(6a))— and—(—C(—R^(5b), —R^(6b))—C(—R^(5c), —R^(6c))—;

wherein R⁵, R^(5a), R^(6a), R^(5b) R^(6b), R^(5c) and R^(6c) areindependently selected from:

H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl,C₀₋₄alkylheteroaryl, C₁₋₄alkylCOOH and C₁₋₄alkylCOOC₁₋₄alkyl, whereinfrom 0-4 hydrogen atoms on the ring atoms of the phenyl, naphthyl andheteroaryl moieties may be independently replaced with a member selectedfrom the group consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —OH, —O—C₁₋₄alkyl, —SH,—S—C₁₋₄alkyl, —CN and —NO₂;

G is selected from:

a direct link, —C(R⁷, R⁸)—, —C(R^(7a), R^(8a))—C(R^(7b), R^(8b)) and—C(R^(7c))═C(R^(8c))—;

wherein R⁷, R⁸, R^(7a), R^(8a), R^(7b), R^(8b), R^(7c) and R^(8c) areindependently a member selected from from the group consisting of:

hydrogen, halogen, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkyl-C₃₋₈cycloalkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, —OR⁹,—N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹, —C₀₋₄alkylC(═O)NR⁹R¹⁰,—C₀₋₄alkylC(═O)NR⁹—CH₂—CH₂—O—R¹⁰, —C₀₋₄alkylC(═O)NR⁹(—CH₂—CH₂—O—R¹⁰—)₂,—N(R⁹)COR¹⁰, N(R⁹)C(═O)R¹⁰, —N(R⁹)SO₂R¹⁰, and a naturally occurring orsynthetic amino acid side chain, wherein from 1-4 hydrogen atoms on thering atoms of the phenyl and naphthyl moieties may be independentlyreplaced with a member selected from the group consisting of halo, —OR⁹,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkyl-C₃₋₈cycloalkyl, —CN and —NO₂;

R⁹ and R¹⁰ are independently selected from:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, wherein from 1-4hydrogen atoms on the ring atoms of the phenyl and naphthyl moieties maybe independently replaced with a member selected from the groupconsisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkyl-C₃₋₈cycloalkyl, —CN and —NO₂, and wherein R⁹ and R¹⁰ takentogether can form a 5-8 membered heterocylic ring;

J is a member selected from the group consisting of:

a direct link, —O—, —O—C(—R¹¹, —R^(11a))—, —S—, —S(═O)—, —S(═O)₂—,—S—C(—R¹¹, —R^(11a))—, —S(═O)—C(—R¹¹, —R^(11a))—, —S(═O)₂—(—R¹¹,—R^(11a))—, —C(═O)—, —C(═O)—N(R^(11b))—, —N(R^(11b))—C(═O)—,—N(R^(11b))—, —N(R^(11b))—C(—R¹¹, —R^(11a))— and a monocyclic aromaticor non-aromatic heterocyclic ring having from 5 to 8 ring atoms, wherein1-4 ring atoms of the ring system are selected from N, O and S, andwherein the ring system may be substituted with 0-2 R^(11c)substituents;

R¹¹, R^(11a), R^(11b) and R^(11c) are a member independently selectedfrom the group consisting of:

hydrogen, halo, —CN, —NO₂, —OH, —O—C₁₋₄alkyl, —O—C₂₋₆alkenyl,—O—C₂₋₆alkynyl, —O—C₃₋₈cycloalkyl, —COOH, —C(═O)—O—C₁₋₄alkyl,—C(═O)—O—C₂₋₆alkenyl, —C(═O)—O—C₂₋₆akynyl, —C(═O)—O—C₃₋₈cycloalkyl,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkyl-C₃₋₈cycloalkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl,C₀₋₄alkylheterocyclic ring having from 1 to 4 hetero ring atoms selectedfrom the group consisting of N, O and S, CH₂COOC₁₋₄alkyl,CH₂COOC₁₋₄alkylphenyl and CH₂COOC₁₋₄alkylnaphthyl;

Y is a member selected from the group consisting of:

(a) phenyl, which is independently substituted with 0-2 R^(1b)substituents;

(b) naphthyl, which is independently substituted with 0-2 R^(1b)substituents; and

(c) a monocyclic or fused bicyclic heterocyclic ring system having from5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system areselected from N, O and S, and wherein the ring system may be substitutedwith 0-2 R^(1b) substituents;

R^(1b) is a member selected from the group consisting of:

halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, NR^(2b)R^(3b), SO₂NR^(2b)R^(3b),SO₂R^(2b), CF₃, OR^(2b), O—CH₂—CH₂—OR^(2b), O—CH₂—COOR^(2b),N(R^(2b))—CH₂—CH₂—OR^(2b), N(—CH₂—CH₂—OR^(2b))₂, N(R^(2b))—C(═O)R^(3b),N(R^(2b))—SO₂R^(3b), and a 5-6 membered aromatic heterocyclic systemcontaining from 1-4 heteroatoms selected from N, O and S, wherein from1-4 hydrogen atoms on the aromatic heterocyclic system may beindependently replaced with a member selected from the group consistingof halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;

R^(2b) and R^(3b) are independently selected from the group consistingof:

H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;

L is selected from:

H, —CN, C(═O)NR¹²R¹³, (CH₂)_(b)NR¹²R¹³, C(═NR¹²)NR¹²R¹³, OR¹²,—NR¹²C(═NR¹²)NR¹²R¹³, and NR¹²C(═NR¹²)—R¹³;

n is an integer from 0 to 8;

R¹² and R¹³ are independently selected from:

hydrogen, —OR¹⁴, —NR¹⁴R¹⁵, C₁₋₄alkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, COOC₁₋₄alkyl, COO—C₀₋₄alkylphenyl andCOO—C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atomsof the phenyl and naphthyl moieties may be independently replaced with amember selected from the group consisting of halo, —OH, —O—C₁₋₄alkyl,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄aklylC₃₋₈cycloalkyl, —CN, and —NO₂;

R¹⁴ and R¹⁵ are independently selected from:

H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

In a further preferred embodiment, the present invention provides acompound according to the formula I:

wherein:

A is selected from:

(a) C₁-C₆-alkyl;

(b) C₃-C₈-cycloalkyl;

(c) phenyl, which is independently substituted with 0-2 R¹ substituents;

(d) naphthyl, which is independently substituted with 0-2 R¹substituents; and

(e) a monocyclic or fused bicyclic heterocyclic ring system having from5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system areselected from N, O and S, and wherein the ring system may be substitutedwith 0-2 R¹ substituents;

R¹ is selected from:

halo, C₁₋₄alkyl, —CN, —NO₂, (CH₂)_(m)NR²R³, SO₂NR²R³, SO₂R², CF₃, OR²,and a 5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from N, O and S;

R² and R³ are independently selected from the group consisting of:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl;

m is an integer of 0-2;

B is a member selected from the group consisting of:

a direct link, —C(═O)—, —N(R⁴)—, —C(═O)—N(R⁴)—, —N(R⁴)—C(═O)—, —SO₂—,—O—, —SO₂—N(R⁴)— and —N(R⁴)—SO₂—;

R⁴ is selected from:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl;

D is phenyl, which is independently substituted with 0-2 R^(1a)substituents;

R^(1a) is selected from:

halo, C₁₋₄alkyl, —CN, —NO₂, —(CH₂)_(m)NR^(2a)R^(3a), —SO₂NR^(2a)R^(3a),—SO₂R^(2a), CF₃, —OR^(2a), and a 5-6 membered aromatic heterocyclicsystem containing from 1-4 heteroatoms selected from N, O and S;

R^(2a) and R^(3a) are independently selected from the group consistingof:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl;

M, D and N collectively form a bicyclic ring structure selected from thegroup consisting of:

 wherein 0 to 2 of the hydrogen atoms on the D portion of the bicyclicring may be replaced by R^(1a) substitutents as defined above;

R¹⁶, R¹⁷, R^(17a), R¹⁸, R^(18a), R^(18b), R¹⁹ and R^(19a) are eachindependently selected from the group consisting of:

halo, C₁₋₄alkyl, —CN, —NO₂, (CH₂)_(m)NR²R³, SO₂NR²R³, SO₂R², CF₃, OR²,and a5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from N, O and S;

R^(17b) and R^(17c) are each independently a member selected from thegroup consisting of:

hydrogen, -halo, hydroxy, —C₁₋₄alkyl, —CN, —NO₂, —(CH₂)_(m)NR²R³,—SO₂NR²R³, —SO₂R², —CF₃, —OR², phenyl, and a 5-6 membered aromaticheterocyclic ring containing from 1-4 heteroatoms selected from N, O andS;

m is an integer from 0-6;

E is a member selected from the group consisting of:

a direct link, —C(═O)—, —C(═O)—N(R⁵)—, —C(—R^(5a),—R^(6a))—and—(—C(—R^(5b),—R^(6b))—C(—R^(5c),—R^(6c))—;

wherein R⁵, R^(5a), R^(6a), R^(5b), R^(6b), R^(5c) and R^(6c) areindependently selected from:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, C₀₋₄alkylheteroaryl,C₁₋₄alkylCOOH and C₁₋₄alkylCOOC₁₋₄alkyl, wherein from 0-2 hydrogen atomson the ring atoms of the phenyl, naphthyl and heteroaryl moieties may beindependently replaced with a member selected from the group consistingof halo, C₁₋₄alkyl, —OH, —O—C₁₋₄alkyl, —SH, —S—C₁₋₄alkyl, —CN and —NO₂;

G is selected from:

a direct link, —C(R⁷,R⁸)—, —C(R^(7a),R^(8a))—C(R^(7b), R^(8b))— and—C(R^(7c))═C(R^(8c))—;

wherein R⁷, R⁸, R^(7a), R^(8a)R^(7b), R^(8b), R^(7c) and R^(8c) areindependently a member selected from from the group consisting of:

hydrogen, halogen, C₁₋₄alkyl, C₀₋₄alkyl—C₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, —OR⁹, —N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹, —C₀₋₄alkylC(═O)NR⁹R¹⁰, —C₀₋₄alkylC(═O)NR⁹—CH₂—CH₂—O—R¹⁰,—C₀₋₄alkyC(═O)NR⁹(—CH₂—CH₂—O—R¹⁰—)₂, —N(R⁹)COR¹⁰,—N(R⁹)C(═O)R¹⁰,—N(R⁹)SO₂R¹⁰, and a naturally occurring or syntheticamino acid side chain;

R⁹ and R¹⁰ are independently selected from:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl;

J is a member selected from the group consisting of:

a direct link, —O—, —O—C(—R¹¹, —R^(11a))—, —S—, —S(═O)₂—, —S—C(—R¹¹,—R^(11a))—, —S(═O)₂—(—R¹¹, —R^(11a))—, —C(═O)—N(R^(11b))—, —N(R^(11b))—,—N(R^(11b))—C(—R¹¹, —R^(11a))— and a monocyclic aromatic or non-aromaticheterocyclic ring having from 5 to 8 ring atoms, wherein 1-4 ring atomsof the ring system are selected from N, O and S, and wherein the ringsystem may be substituted with 0-2 R^(11c) substituents;

R¹¹, R^(11a), R^(11b) and R^(11c) are a member independently selectedfrom the group consisting of:

hydrogen, halo, —CN, —NO₂, —OH, —O—C₁₄alkyl, —O—C₃₋₈cycloalkyl, —COOH,—C(═O)—O—C₁₋₄alkyl, —C(═O)—O—C₃₋₈cycloalkyl, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₀₋₄alkyl—C₃₋₈cycloalkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, and aC₀₋₄alkyl heterocyclic ring having from 1 to 4 hetero ring atomsselected from the group consisting of N, O and S, CH₂COOC₁₋₄alkyl, CH₂COOC₁₋₄alkylphenyl and CH₂ COOC₁₋₄alkylnaphthyl;

Y is a member selected from the group consisting of:

(a) phenyl, which is independently substituted with 0-2 R^(1b)substituents;

(b) naphthyl, which is independently substituted with 0-2 R^(1b)substituents; and

(c) a monocyclic or fused bicyclic heterocyclic ring system having from5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system areselected from N, O and S, and wherein the ring system may be substitutedwith 0-2 R^(1b) substituents;

R^(1b) is a member selected from the group consisting of:

halo, C₁₋₄ alky1, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, NR^(2b) R^(3b), SO₂ R^(2b), CF₃,OR^(2b), O—CH₂—CH₂—OR^(2b), O—CH₂—COOR^(2b), N(R^(2b))—CH₂—CH₂—OR^(2b),N(—CH₂—CH₂—OR^(2b)) ₂, N(R^(2b))—C(═O)R^(3b), N(R^(2b))—SO₂—R^(3b), anda 5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from N, O and S, wherein from 1-4 hydrogen atoms onthe aromatic heterocyclic system may be independently replaced with amember selected from the group consisting of halo, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CNand —NO₂;

R^(2b)and R^(3b)are independently selected from the group consisting of:

H, C₁₋₄alkyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyland C₀₋₄alkylnaphthyl;

L is selected from:

H, —CN, C(═O)NR¹²R¹³, (CH₂)_(n)NR¹²R¹³, C(═NR¹²) NR¹²R¹³, OR¹²,—NR¹²C(═NR¹²)NR¹²R¹³, and NR¹²C(═NR¹²)—R¹³;

n is an integer from 0 to 6;

R¹²and R¹³are independently selected from:

hydrogen, —OR¹⁴, —NR¹⁴R¹⁵, C₁₋₄alky, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl,COOC₁₋₄alkyl, COO—Co₀₋₄alkylphenyl and COO—CO₀₋₄alkylnaphthyl, whereinfrom 0-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, —OH, —O—C₁₋₄alkyl, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;

R¹⁴and R¹⁵are independently selected from:

H, C₁₋₄alkyl, C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl andC₀₋₄alkylnaphthyl;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof

In a still further preferred embodiment, the present invention providesa compound according to the formula I:

wherein:

A is selected from:

(a) phenyl, which is independently substituted with 0-2 R¹substituents;and

(b) a monocyclic or fused bicyclic heterocyclic ring system having from5 to 10 ring atoms, wherein 1-4 ring atoms of the ring system areselected from N, O and S, and wherein the ring system may be substitutedwith 0-2 R¹substituents;

R¹is selected from:

halo, (CH₂)_(m)NR²R³, SO₂NR²R³and SO₂R²;

R²and R³are independently selected from the group consisting of:

H and C₁₋₄alkyl;

m is an integer of 0-2;

Q is a member selected from the group consisting of:

a direct link, —C(═O)—, —SO₂—, and —O—;

D is phenyl, which is independently substituted with 0-2 R^(1a)substituents;

R^(1a) is selected from:

halo and C₁₋₄alkyl;

M, D and N collectively form a bicyclic ring structure selected from thegroup consisting of:

R¹⁶, R¹⁷, R^(17a), R¹⁸, R^(18a), ¹⁸ R¹⁹ and R^(19a) are eachindependently selected from the group consisting of:

halo, C₁₋₄alkyl, —CN, —NO₂, (CH₂)_(m)NR²R³, SO₂NR²R³, SO₂R², CF₃ andOR²;

R^(17b) and R^(17c) are each independently a member selected from thegroup consisting of:

hydrogen, —halo, hydroxy, —C₁₋₄alkyl, —CN, —NO₂, —(CH₂)_(m)NR²R³,—SO₂NR²R³, —SO₂R², —CF₃, —OR², phenyl, and a 5-6 membered aromaticheterocyclic ring containing from 1-3 N atoms;

E is a member selected from the group consisting of:

a direct link, —C(═O)—, —C(═O)—N(R⁵)—, —C(—R^(5a),—R^(6a))—and—(—C(—R^(5b),—R^(6b))—C(—R^(5c),—R^(6c))—;

wherein R⁵, R^(5a), R^(6a), R^(5b)R^(6b), R^(5c) and R^(6c) areindependently selected from:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, C₀₋₄alkylheteroaryl,C₁₋₄alkylCOOH and C₁₋₄alkylCOOC₁₋₄alkyl;

G is selected from:

a direct link, —C(R⁷,R⁸)—, —C(R^(7a),R^(8a))—C(R^(7b),R^(8b))—and—C(R^(7c))═C(R^(8c))—;

wherein R⁷, R⁸, R^(7a), R^(8a), R^(7b), R^(8b), R^(7c) and R^(8c) areindependently a member selected from from the group consisting of:

hydrogen, halogen, C₁₋₄alkyl, C₀₋₄alkyl—C₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, —OR⁹, —N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹,—C₀₋₄alkyC(═O)NR⁹R¹⁰, —CO₀₋₄alkylC(═O)NR⁹—CH₂—CH₂—O—R¹⁰,—C₀₋₄alkylC(═O)NR⁹(—CH₂—CH₂—O—R¹⁰—)₂, —N(R⁹)COR¹⁰,—N(R⁹)C(═O)R¹⁰,—N(R⁹)SO₂R¹⁰, and a naturally occurring or syntheticamino acid side chain;

R⁹ and R¹⁰ are independently selected from:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl;

J is a member selected from the group consisting of:

a direct link, —O—, —S—, —C(═O)—N(R^(11b))—, —N(R^(11b))—,—N(R^(11b))—C(—R¹¹, —R^(11a)) and a monocyclic aromatic or non-aromaticheterocyclic ring having from 5 to 8 ring atoms, wherein 1-4 ring atomsof the ring system are selected from N, O and S, and wherein the ringsystem may be substituted with 0-2 R^(11c) substituents;

R¹¹, R^(11a), R^(11b) and R^(11c) are a member independently selectedfrom the group consisting of:

hydrogen, halo, —CN, —NO₂, —OH, —O—C₁₋₄alkyl, —O—C₃₋₈cycloalkyl, —COOH,—C(═O)—O—C₁₋₄alkyl, —C(═O)—O—C₃₋₈cycloalkyl, C₁₋₄alky, C₃₋₈cycloalkyl,C₀₋₄alkyl—C₃₋₈cycloalkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, and aC₀₋₄alkyl heterocyclic ring having from 1 to 4 hetero ring atomsselected from the group consisting of N, O and S, CH₂COOC₁₋₄alkyl,CH₂COOC₁₋₄alkylphenyl and CH₂COOC₁₋₄alkylnaphthyl;

Y is a member selected from the group consisting of:

(a) phenyl, which is independently substituted with 0-2 R^(1b)substituents;

(b) an aromatic heterocyclic ring having from 5 to 10 ring atoms,wherein 1-4 ring atoms of the ring system are selected from N, O and S,and wherein the ring may be substituted with 0-2 R^(1b) substituents;

(c) a fused aromatic bicyclic heterocyclic ring system having from 5 to10 ring atoms, wherein 1-4 ring atoms of the ring system are selectedfrom N, O and S, and wherein the bicyclic ring system may be substitutedwith 0-2 R^(1b) substituents;

R^(1b) is a member selected from the group consisting of:

halo, —C₁₋₄alkyl, —OH, —OBn, —O—CH₂—CH₂—OH, —O—CH₂—CH₂—OCH₃,—O—CH₂—COOH, —O—CH₂—C(═O)—O—CH₃, —NH₂, —NH—CH₂—CH₂—O—CH₃,—NH—C(═O)—O—CH₃ and —NH—SO₂—CH₃;

L is selected from:

H, —C(═O)NR¹²R¹³, —(CH₂)_(n)NR¹²R¹³ and —C(═NR¹²)NR¹²R¹³;

n is an integer from 0 to 6;

R¹² and R^(—)are independently selected from:

hydrogen and C₁₋₄alkyl;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof

In yet another preferred embodiment, the present invention provides acompound according to formula I:

wherein:

A is a member selected from the group consisting of:

D is a member selected from the group consisting of:

E is a member selected from the group consisting of

a direct link, —C(═O)—, —C(═O)—N(R⁵)—, —C(—R^(5a),—R^(6a))—and—(—C(—R^(5b),—R^(6b))—C(—R^(5c),—R^(6c))—;

wherein R⁵, R^(5a), R^(6a), R^(5b) R^(6b), R^(5c) and R^(6c) areindependently selected from:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, C₀₋₄alkylheteroaryl,C₁₋₄alkylCOOH and C₁₋₄alkylCOOC₁₋₄alkyl;

G is selected from:

a direct link, —C(R⁷,R⁸)—, —C(R^(7a),R^(8a))—C(R^(7b),R^(8b))—and—C(R^(7c))═C(R^(8c))—;

wherein R⁷, R⁸, R^(7a), R^(8a), R^(7b), R^(8b), R^(7c) and R^(8c) areindependently a member selected from from the group consisting of:

hydrogen, halogen, C₁₋₄alkyl C₀₋₄alkyl—C₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, —OR⁹, —N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹,—C₀₋₄alkylC(═O)NR⁹R¹⁰, —C₀₋₄alkylC(═O)NR⁹—CH₂—CH₂—O—R¹⁰, —C₀₋₄alkylC(═O)NR⁹(—CH₂—CH₂—O—R¹⁰—)₂, —N(R⁹)COR¹⁰, —N(R⁹)C(═O)R¹⁰,—N(R⁹)SO₂R¹⁰, anda naturally occurring or synthetic amino acid side chain;

R⁹ and R¹⁰ are independently selected from:

H, C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl;

J is a member selected from the group consisting of:

a direct link, —O—, —S—, —C(═O)—N(R^(11b))—, —N(R^(11b))—, —N(R^(11b))—C(—R¹¹, —R^(11a))—and a monocyclic aromatic or non-aromatic heterocyclicring having from 5 to 8 ring atoms, wherein 1-4 ring atoms of the ringsystem are selected from N, O and S, and wherein the ring system may besubstituted with 0-2 R^(11c) substitutuents;

R¹¹, R^(11a), R^(11b) and R^(11c) are a member independently selectedfrom the group consisting of:

hydrogen, halo, —CN, —NO₂, —OH, —O—C₁₋₄alkyl, —C₁₋₄alkyl, —COOH,phenyl,and benzyl wherein the aromatic ring of the phenyl or benzyl issubstituted with 0-2 members independently selected from the groupconsisting of halo, —CN, —NO₂, —OH, —O—C₁₋₄alkyl, —C₁₋₄alkyl, —COOH and—C(═O)—O—C₁₋₄alkyl;

Y and L taken together are a member selected from the group consistingof:

M and Q are as defined elsewhere in the specification;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

The following non-limiting tables illustrate representative compounds ofthe present invention wherein the “Y-L” portions for each of the formulain each of the tables are taken together and are independently selectedfrom the group consisting of:

TABLE 1

Formula II R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1a

Formula IIa R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1b

Formula IIb R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1c

Formula IIc R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1d

Formula IId R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1e

Formula IIe R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1f

Formula IIf R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1g

Formula IIg R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1h

Formula IIh R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1i

Formula IIi R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1j

Formula IIj R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1k

Formula IIk R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1(l)

Formula II(l) R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1m

Formula IIm R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1n

Formula IIn R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1o

Formula IIo R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1p

Formula IIp R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 1q

Formula IIq R⁷ R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 2

Formula III R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2a

Formula IIIa R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2b

Formula IIIb R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2c

Formula IIIc R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2d

Formula IIId R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2e

Formula IIIe R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2f

Formula IIIf R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2g

Formula IIIg R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2h

Formula IIIh R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2i

Formula IIIi R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2j

Formula IIIj R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2k

Formula IIIk R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2(l)

Formula III(l) R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2m

Formula IIIm R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2n

Formula IIIn R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2o

Formula IIIo R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2p

Formula IIIp R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 2q

Formula IIIq R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 3

Formula IV R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3a

Formula IVa R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3b

Formula IVb R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3c

Formula IVc R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3d

Formula IVd R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3e

Formula IVe R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3f

Formula IVf R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3g

Formula IVg R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3h

Formula IVh R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3i

Formula IVi R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3j

Formula IVj R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3k

Formula IVk R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3(l)

Formula IV(l) R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3m

Formula IVm R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3n

Formula IVn R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3o

Formula IVo R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3p

Formula IVp R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 3q

Formula IVq R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4 Formula V

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4a Formula Va

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4b Formula Vb

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4c Formula Vc

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4d Formula Vd

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4e Formula Ve

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4f Formula Vf

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4g Formula Vg

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4h Formula Vh

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4i Formula Vi

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4j Formula Vj

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4k Formula Vk

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4(l) Formula V(l)

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4m Formula Vm

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4n Formula Vn

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4o Formula Vo

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4p Formula Vp

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 4q Formula Vq

R^(11c1) R^(11c2) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5

Formula VI R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5a

Formula VIa R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5b

Formula VIb R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5c

Formula VIc R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5d

Formula VId R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5e

Formula VIe R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5f

Formula VIf R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5g

Formula VIg R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5h

Formula VIh R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5i

Formula VIi R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5j

Formula VIj R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5k

Formula VIk R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5(l)

Formula VI(l) R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5m

Formula VIm R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5n

Formula VIn R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5o

Formula VIo R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5p

Formula VIp R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 5q

Formula VIq R^(7c) R^(8c) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6 Formula VII

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6a Formula VIIa

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6b Formula VIIb

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6c Formula VIIc

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6d Formula VIId

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6e Formula VIIe

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6f Formula VIIf

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6g Formula VIIg

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6h Formula VIIh

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6i Formula VIIi

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6j Formula VIIj

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6k Formula VIIk

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6(l) Formula VII(l)

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6m Formula VIIm

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6n Formula VIIn

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6o Formula VIIo

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6p Formula VIIp

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 6q Formula VIIq

R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7

Formula VIII R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7a

Formula VIIIa R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7b

Formula VIIIb R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7c

Formula VIIIc R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7d

Formula VIIId R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7e

Formula VIIIe R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7f

Formula VIIIf R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7g

Formula VIIIg R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7h

Formula VIIIh R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7i

Formula VIIIi R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7j

Formula VIIIj R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7k

Formula VIIIk R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7(l)

Formula VIII(l) R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7m

Formula VIIIm R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7n

Formula VIIIn R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7o

Formula VIIIo R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7p

Formula VIIIp R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 7q

Formula VIIIq R^(7a) R^(7b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 8 Formula IX

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8a Formula IXa

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8b Formula IXb

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8c Formula IXc

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8d Formula IXd

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8e Formula IXe

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8f Formula IXf

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8g Formula IXg

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8h Formula IXh

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8i Formula IXi

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8j Formula IXj

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8k Formula IXk

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8(l) Formula IX(l)

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8m Formula IXm

R^(6c) R^(11b) H H Me Me

OMe H OMe Me F H —OH Me Br Me —NH2 H OCH2Ph H OCH2CH2OMe H H Et Me Et

TABLE 8n Formula IXn

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8o Formula IXo

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8p Formula IXp

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 8q Formula IXq

R^(6c) R^(11b) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9

Formula X R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9a

Formula Xa R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9b

Formula Xb R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9c

Formula Xc R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9d

Formula Xd R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9e

Formula Xe R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9f

Formula Xf R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9g

Formula Xg R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9h

Formula Xh R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9i

Formula Xi R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9j

Formula Xj R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9k

Formula Xk R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9(l)

Formula X(l) R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9m

Formula Xm R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9n

Formula Xn R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9o

Formula Xo R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9p

Formula Xp R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 9q

Formula Xq R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10 Formula XI

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10a Formula XIa

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10b Formula XIb

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10c Formula XIc

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10d Formula XId

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10e Formula XIe

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10f Formula XIf

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10g Formula XIg

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10h Formula XIh

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10i Formula XIi

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10j Formula XIj

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10k Formula XIk

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10(l) Formula XI(l)

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10m Formula XIm

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10n Formula XIn

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10o Formula XIo

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10p Formula XIp

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 10q Formula XIq

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11 Formula XII

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11a Formula XIa

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11b Formula XIb

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11c Formula XIc

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11d Formula XIId

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11e Formula XIIe

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11f Formula XIIf

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11g Formula XIIg

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11h Formula XIIh

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11i Formula XIIi

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11j Formula XIIj

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11k Formula XIIk

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11(l) Formula XII(l)

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11m Formula XIIm

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11n Formula XIIn

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11o Formula XIIo

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11p Formula XIIp

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

TABLE 11q Formula XIIq

R^(11c1) R^(11c2) H H Me Me Br Me H Cl Me Cl Et Cl

OCH2Ph H OCH2CH2OMe H Me F Me H SO2Me H OMe H OMe Me F H Et H —OH Me EtBr

—NH2 H H Et Et F Me Et SO2Me Cl

Also preferred are compounds according to Tables 1 through Table 11q,wherein

the biphenylene portions of their formulae:

are each replaced with the following ring structure:

wherein each of the A and D ring portions are as follows:

A D

Even more preferred compounds are set forth in Tables 12-24, below.

TABLE 12

TABLE 13

TABLE 14

TABLE 15

TABLE 16

TABLE 17

 wherein A—Q— is selected from the group consisting of:

t-Bu; O-t-Bu; —(CH₂)₀₋₅-amino; OH; carboxylic acid ester; carboxamide;

TABLE 18

TABLE 19

TABLE 20

TABLE 21

TABLE 22

TABLE 23

TABLE 24

TABLE 25

TABLE 26

TABLE 27

Wherein:

Q is a direct link, and A is a member selected from the group:

 or Q is a —C(═NH)— group, and A is a member selected from the group:

 G is a direct link;

J is a member selected from the group:

Y—L is a member selected from the group:

This invention also encompasses all pharmaceutically acceptable isomers,salts, hydrates and solvates of the compounds of formula I. In addition,the compounds of formula I can exist in various isomeric and tautomericforms, and all such forms are meant to be included in the invention,along with pharmaceutically acceptable salts, hydrates and solvates ofsuch isomers and tautomers.

The compounds of this invention may be isolated as the free acid or baseor converted to salts of various inorganic and organic acids and bases.Such salts are within the scope of this invention. Non-toxic andphysiologically compatible salts are particularly useful although otherless desirable salts may have use in the processes of isolation andpurification.

A number of methods are useful for the preparation of the saltsdescribed above and are known to those skilled in the art. For example,the free acid or free base form of a compound of one of the formulasabove can be reacted with one or more molar equivalents of the desiredacid or base in a solvent or solvent mixture in which the salt isinsoluble, or in a solvent like water after which the solvent is removedby evaporation, distillation or freeze drying. Alternatively, the freeacid or base form of the product may be passed over an ion exchangeresin to form the desired salt or one salt form of the product may beconverted to another using the same general process.

Prodrug Derivatives of Compounds

This invention also encompasses prodrug derivatives of the compoundscontained herein. The term “prodrug” refers to a pharmacologicallyinactive derivative of a parent drug molecule that requiresbiotransformation, either spontaneous or enzymatic, within the organismto release the active drug. Prodrugs are variations or derivatives ofthe compounds of this invention which have groups cleavable undermetabolic conditions. Prodrugs become the compounds of the inventionwhich are pharmaceutically active in vivo, when they undergo solvolysisunder physiological conditions or undergo enzymatic degradation. Prodrugcompounds of this invention may be called single, double, triple etc.,depending on the number of biotransformation steps required to releasethe active drug within the organism, and indicating the number offunctionalities present in a precursor-type form. Prodrug forms oftenoffer advantages of solubility, tissue compatibility, or delayed releasein the mammalian organism (see, Bundgard, Design of Prodrugs, pp. 7-9,21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry ofDrug Design and Drug Action, pp. 352-401, Academic Press, San Diego,Calif., 1992). Prodrugs commonly known in the art include acidderivatives well known to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acids with a suitablealcohol, or amides prepared by reaction of the parent acid compound withan amine, or basic groups reacted to form an acylated base derivative.Moreover, the prodrug derivatives of this invention may be combined withother features herein taught to enhance bioavailability.

As mentioned above, the compounds of this invention find utility astherapeutic agents for disease states in mammals which have disorders ofcoagulation such as in the treatment or prevention of unstable angina,refractory angina, myocardial infarction, transient ischemic attacks,thrombotic stroke, embolic stroke, disseminated intravascularcoagulation including the treatment of septic shock, deep venousthrombosis in the prevention of pulmonary embolism or the treatment ofreocclusion or restenosis of reperfused coronary arteries. Further,these compounds are useful for the treatment or prophylaxis of thosediseases which involve the production and/or action of factorXa/prothrombinase complex. This includes a number of thrombotic andprothrombotic states in which the coagulation cascade is activated whichinclude but are not limited to, deep venous thrombosis, pulmonaryembolism, myocardial infarction, stroke, thromboembolic complications ofsurgery and peripheral arterial occlusion.

Accordingly, a method for preventing or treating a condition in a mammalcharacterized by undesired thrombosis comprises administering to themammal a therapeutically effective amount of a compound of thisinvention. In addition to the disease states noted above, other diseasestreatable or preventable by the administration of compounds of thisinvention include, without limitation, occlusive coronary thrombusformation resulting from either thrombolytic therapy or percutaneoustransluminal coronary angioplasty, thrombus formation in the venousvasculature, disseminated intravascular coagulopathy, a conditionwherein there is rapid consumption of coagulation factors and systemiccoagulation which results in the formation of life-threatening thrombioccurring throughout the microvasculature leading to widespread organfailure, hemorrhagic stroke, renal dialysis, blood oxygenation, andcardiac catheterization.

The compounds of the invention also find utility in a method forinhibiting the coagulation of biological samples, (e.g. blood) whichcomprises the administration of a compound of the invention.

The compounds of the present invention may also be used in combinationwith other therapeutic or diagnostic agents. In certain preferredembodiments, the compounds of this invention may be coadministered alongwith other compounds typically prescribed for these conditions accordingto generally accepted medical practice such as anticoagulant agents,thrombolytic agents, or other antithrombotics, including plateletaggregation inhibitors, tissue plasminogen activators, urokinase,prourokinase, streptokinase, heparin, aspirin, or warfarin. Thecompounds of the present invention may act in a synergistic fashion toprevent reocclusion following a successful thrombolytic therapy and/orreduce the time to reperfusion. These compounds may also allow forreduced doses of the thrombolytic agents to be used and thereforeminimize potential hemorrhagic side-effects. The compounds of thisinvention can be utilized in vivo, ordinarily in mammals such asprimates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, ratsand mice, or in vitro.

The biological properties of the compounds of the present invention canbe readily characterized by methods that are well known in the art, forexample by the in vitro protease activity assays and in vivo studies toevaluate antithrombotic efficacy, and effects on hemostasis andhematological parameters, such as are illustrated in the examples.

Diagnostic applications of the compounds of this invention willtypically utilize formulations in the form of solutions or suspensions.In the management of thrombotic disorders the compounds of thisinvention may be utilized in compositions such as tablets, capsules orelixirs for oral administration, suppositories, sterile solutions orsuspensions or injectable administration, and the like, or incorporatedinto shaped articles. Subjects in need of treatment (typicallymammalian) using the compounds of this invention can be administereddosages that will provide optimal efficacy. The dose and method ofadministration will vary from subject to subject and be dependent uponsuch factors as the type of mammal being treated, its sex, weight, diet,concurrent medication, overall clinical condition, the particularcompounds employed, the specific use for which these compounds areemployed, and other factors which those skilled in the medical arts willrecognize.

Formulations of the compounds of this invention are prepared for storageor administration by mixing the compound having a desired degree ofpurity with physiologically acceptable carriers, excipients, stabilizersetc., and may be provided in sustained release or timed releaseformulations. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical field, and are described, for example,in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R.Gennaro edit. 1985). Such materials are nontoxic to the recipients atthe dosages and concentrations employed, and include buffers such asphosphate, citrate, acetate and other organic acid salts, antioxidantssuch as ascorbic acid, low molecular weight (less than about tenresidues) peptides such as polyarginine, proteins, such as serumalbumin, gelatin, or immunoglobulins, hydrophilic polymers such aspolyvinylpyrrolidinone, amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannoseor dextrins, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as Tween, Pluronics or polyethyleneglycol.

Dosage formulations of the compounds of this invention to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in lyophilized form or as an aqueous solution. The pH of thepreparations of this invention typically will be 3-11, more preferably5-9 and most preferably 7-8. It will be understood that use of certainof the foregoing excipients, carriers, or stabilizers will result in theformation of cyclic polypeptide salts. While the preferred route ofadministration is by injection, other methods of administration are alsoanticipated such as orally, intravenously (bolus and/or infusion),subcutaneously, intramuscularly, colonically, rectally, nasally,transdermally or intraperitoneally, employing a variety of dosage formssuch as suppositories, implanted pellets or small cylinders, aerosols,oral dosage formulations and topical formulations such as ointments,drops and dermal patches. The compounds of this invention are desirablyincorporated into shaped articles such as implants which may employinert materials such as biodegradable polymers or synthetic silicones,for example, Silastic, silicone rubber or other polymers commerciallyavailable.

The compounds of the invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of lipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of this invention may also be delivered by the use ofantibodies, antibody fragments, growth factors, hormones, or othertargeting moieties, to which the compound molecules are coupled. Thecompounds of this invention may also be coupled with suitable polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidinone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, compounds of theinvention may be coupled to a class of biodegradable polymers useful inachieving controlled release of a drug, for example polylactic acid,polyglycolic acid, copolymers of polylactic and polyglycolic acid,polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters,polyacetals, polydihydropyrans, polycyanoacrylates and cross linked oramphipathic block copolymers of hydrogels. Polymers and semipermeablepolymer matrices may be formed into shaped articles, such as valves,stents, tubing, prostheses and the like.

Thetapeutic compound liquid formulations generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by hypodermic injectionneedle.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill be influenced by the route of administration, the therapeuticobjectives and the condition of the patient. For injection by hypodermicneedle, it may be assumed the dosage is delivered into the body'sfluids. For other routes of administration, the absorption efficiencymust be individually determined for each compound by methods well knownin pharmacology. Accordingly, it may be necessary for the therapist totiter the dosage and modify the route of administration as required toobtain the optimal therapeutic effect. The determination of effectivedosage levels, that is, the dosage levels necessary to achieve thedesired result, will be readily determined by one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved.

The compounds of the invention can be administered orally orparenterally in an effective amount within the dosage range of about 0.1to 100 mg/kg, preferably about 0.5 to 50 mg/kg and more preferably about1 to 20 mg/kg on a regimen in a single or 2 to 4 divided daily dosesand/or continuous infusion.

Typically, about 5 to 500 mg of a compound or mixture of compounds ofthis invention, as the free acid or base form or as a pharmaceuticallyacceptable salt, is compounded with a physiologically acceptablevehicle, carrier, excipient, binder, preservative, stabilizer, dye,flavor etc., as called for by accepted pharmaceutical practice. Theamount of active ingredient in these compositions is such that asuitable dosage in the range indicated is obtained.

Typical adjuvants which may be incorporated into tablets, capsules andthe like are binders such as acacia, corn starch or gelatin, andexcipients such as microcrystalline cellulose, disintegrating agentslike corn starch or alginic acid, lubricants such as magnesium stearate,sweetening agents such as sucrose or lactose, or flavoring agents. Whena dosage form is a capsule, in addition to the above materials it mayalso contain liquid carriers such as water, saline, or a fatty oil.Other materials of various types may be used as coatings or as modifiersof the physical form of the dosage unit. Sterile compositions forinjection can be formulated according to conventional pharmaceuticalpractice. For example, dissolution or suspension of the active compoundin a vehicle such as an oil or a synthetic fatty vehicle like ethyloleate, or into a liposome may be desired. Buffers, preservatives,antioxidants and the like can be incorporated according to acceptedpharmaceutical practice.

Preparation of Compounds

The compounds of the present invention may be synthesized by eithersolid or liquid phase methods described and referenced in standardtextbooks, or by a combination of both methods. These methods are wellknown in the art. See, Bodanszky, “The Principles of Peptide Synthesis”,Hafner, et al., Eds., Springer-Verlag, Berlin, 1984.

Starting materials used in any of these methods are commerciallyavailable from chemical vendors such as Aldrich, Sigma, NovaBiochemicals, Bachem Biosciences, and the like, or may be readilysynthesized by known procedures.

Reactions are carried out in standard laboratory glassware and reactionvessels under reaction conditions of standard temperature and pressure,except where otherwise indicated.

During the synthesis of these compounds, the functional groups of theamino acid derivatives used in these methods are protected by blockinggroups to prevent cross reaction during the coupling procedure. Examplesof suitable blocking groups and their use are described in “ThePeptides: Analysis, Synthesis, Biology”, Academic Press, Vol. 3 (Gross,et al., Eds., 1981) and Vol. 9 (1987), the disclosures of which areincorporated herein by reference.

Non-limiting exemplary synthesis schemes are outlined directly below,and specific steps are described in the Examples. The reaction productsare isolated and purified by conventional methods, typically by solventextraction into a compatible solvent. The products may be furtherpurified by column chromatography or other appropriate methods.

Compositions and Formulations

The compounds of this invention may be isolated as the free acid or baseor converted to salts of various inorganic and organic acids and bases.Such salts are within the scope of this invention. Non-toxic andphysiologically compatible salts are particularly useful although otherless desirable salts may have use in the processes of isolation andpurification.

A number of methods are useful for the preparation of the saltsdescribed above and are known to those skilled in the art. For example,reaction of the free acid or free base form of a compound of thestructures recited above with one or more molar equivalents of thedesired acid or base in a solvent or solvent mixture in which the saltis insoluble, or in a solvent like water after which the solvent isremoved by evaporation, distillation or freeze drying. Alternatively,the free acid or base form of the product may be passed over an ionexchange resin to form the desired salt or one salt form of the productmay be converted to another using the same general process.

Diagnostic applications of the compounds of this invention willtypically utilize formulations such as solution or suspension. In themanagement of thrombotic disorders the compounds of this invention maybe utilized in compositions such as tablets, capsules or elixirs fororal administration, suppositories, sterile solutions or suspensions orinjectable administration, and the like, or incorporated into shapedarticles. Subjects in need of treatment (typically mammalian) using thecompounds of this invention can be administered dosages that willprovide optimal efficacy. The dose and method of administration willvary from subject to subject and be dependent upon such factors as thetype of mammal being treated, its sex, weight, diet, concurrentmedication, overall clinical condition, the particular compoundsemployed, the specific use for which these compounds are employed, andother factors which those skilled in the medical arts will recognize.

Formulations of the compounds of this invention are prepared for storageor administration by mixing the compound having a desired degree ofpurity with physiologically acceptable carriers, excipients, stabilizersetc., and may be provided in sustained release or timed releaseformulations. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical field, and are described, for example,in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R.Gennaro edit. 1985). Such materials are nontoxic to the recipients atthe dosages and concentrations employed, and include buffers such asphosphate, citrate, acetate and other organic acid salts, antioxidantssuch as ascorbic acid, low molecular weight (less than about tenresidues) peptides such as polyarginine, proteins, such as serumalbumin, gelatin, or immunoglobulins, hydrophilic polymers such aspolyvinylpyrrolidinone, amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannoseor dextrins, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as Tween, Pluronics or polyethyleneglycol.

Dosage formulations of the compounds of this invention to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in lyophilized form or as an aqueous solution. The pH of thepreparations of this invention typically will be between 3 and 11, morepreferably from 5 to 9 and most preferably from 7 to 8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of cyclic polypeptide salts.While the preferred route of administration is by injection, othermethods of administration are also anticipated such as intravenously(bolus and/or infusion), subcutaneously, intramuscularly, colonically,rectally, nasally or intraperitoneally, employing a variety of dosageforms such as suppositories, implanted pellets or small cylinders,aerosols, oral dosage formulations and topical formulations such asointments, drops and dermal patches. The compounds of this invention aredesirably incorporated into shaped articles such as implants which mayemploy inert materials such as biodegradable polymers or syntheticsilicones, for example, Silastic, silicone rubber or other polymerscommercially available.

The compounds of this invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of lipids, such as cholesterol, stearylamine orphosphatidylcholines.

The compounds of this invention may also be delivered by the use ofantibodies, antibody fragments, growth factors, hormones, or othertargeting moieties, to which the compound molecules are coupled. Thecompounds of this invention may also be coupled with suitable polymersas targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the factor Xainhibitors of this invention may be coupled to a class of biodegradablepolymers useful in achieving controlled release of a drug, for examplepolylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcross linked or amphipathic block copolymers of hydrogels. Polymers andsemipermeable polymer matrices may be formed into shaped articles, suchas valves, stents, tubing, prostheses and the like.

Therapeutic compound liquid formulations generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by hypodermic injectionneedle.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill naturally be influenced by the route of administration, thetherapeutic objectives, and the condition of the patient. For injectionby hypodermic needle, it may be assumed the dosage is delivered into thebody's fluids. For other routes of administration, the absorptionefficiency must be individually determined for each inhibitor by methodswell known in pharmacology. Accordingly, it may be necessary for thetherapist to titer the dosage and modify the route of administration asrequired to obtain the optimal therapeutic effect. The determination ofeffective dosage levels, that is, the dosage levels necessary to achievethe desired result, will be within the ambit of one skilled in the art.Typically, applications of compound are commenced at lower dosagelevels, with dosage levels being increased until the desired effect isachieved.

A typical dosage might range from about 0.001 mg/kg to about 1000 mg/kg,preferably from about 0.01 mg/kg to about 100 mg/kg, and more preferablyfrom about 0.10 mg/kg to about 20 mg/kg. Advantageously, the compoundsof this invention may be administered several times daily, and otherdosage regimens may also be useful.

Typically, about 0.5 to 500 mg of a compound or mixture of compounds ofthis invention, as the free acid or base form or as a pharmaceuticallyacceptable salt, is compounded with a physiologically acceptablevehicle, carrier, excipient, binder, preservative, stabilizer, dye,flavor etc., as called for by accepted pharmaceutical practice. Theamount of active ingredient in these compositions is such that asuitable dosage in the range indicated is obtained.

Typical adjuvants which may be incorporated into tablets, capsules andthe like are a binder such as acacia, corn starch or gelatin, andexcipient such as microcrystalline cellulose, a disintegrating agentlike corn starch or alginic acid, a lubricant such as magnesiumstearate, a sweetening agent such as sucrose or lactose, or a flavoringagent. When a dosage form is a capsule, in addition to the abovematerials it may also contain a liquid carrier such as water, saline, afatty oil. Other materials of various types may be used as coatings oras modifiers of the physical form of the dosage unit. Sterilecompositions for injection can be formulated according to conventionalpharmaceutical practice. For example, dissolution or suspension of theactive compound in a vehicle such as an oil or a synthetic fatty vehiclelike ethyl oleate, or into a liposome may be desired. Buffers,preservatives, antioxidants and the like can be incorporated accordingto accepted pharmaceutical practice.

In practicing the methods of this invention, the compounds of thisinvention may be used alone or in combination, or in combination withother therapeutic or diagnostic agents. In certain preferredembodiments, the compounds of this inventions may be coadministeredalong with other compounds typically prescribed for these conditionsaccording to generally accepted medical practice, such as anticoagulantagents, thrombolytic agents, or other antithrombotics, includingplatelet aggregation inhibitors, tissue plasminogen activators,urokinase, prourokinase, streptokinase, heparin, aspirin, or warfarin.The compounds of this invention can be utilized in vivo, ordinarily inmammals such as primates, such as humans, sheep, horses, cattle, pigs,dogs, cats, rats and mice, or in vitro.

The preferred compounds of the present invention are characterized bytheir ability to inhibit thrombus formation with acceptable effects onclassical measures of coagulation parameters, platelets and plateletfunction, and acceptable levels of bleeding complications associatedwith their use. Conditions characterized by undesired thrombosis wouldinclude those involving the arterial and venous vasculature.

With respect to the coronary arterial vasculature, abnormal thrombusformation characterizes the rupture of an established atheroscleroticplaque which is the major cause of acute myocardial infarction andunstable angina, as well as also characterizing the occlusive coronarythrombus formation resulting from either thrombolytic therapy orpercutaneous transluminal coronary angioplasty (PTCA).

With respect to the venous vasculature, abnormal thrombus formationcharacterizes the condition observed in patients undergoing majorsurgery in the lower extremities or the abdominal area who often sufferfrom thrombus formation in the venous vasculature resulting in reducedblood flow to the affected extremity and a predisposition to pulmonaryembolism. Abnormal thrombus formation further characterizes disseminatedintravascular coagulopathy commonly occurs within both vascular systemsduring septic shock, certain viral infections and cancer, a conditionwherein there is rapid consumption of coagulation factors and systemiccoagulation which results in the formation of life-threatening thrombioccurring throughout the microvasculature leading to widespread organfailure.

The compounds of this present invention, selected and used as disclosedherein, are believed to be useful for preventing or treating a conditioncharacterized by undesired thrombosis, such as (a) the treatment orprevention of any thrombotically mediated acute coronary syndromeincluding myocardial infarction, unstable angina, refractory angina,occlusive coronary thrombus occurring post-thrombolytic therapy orpost-coronary angioplasty, (b) the treatment or prevention of anythrombotically mediated cerebrovascular syndrome including embolicstroke, thrombotic stroke or transient ischemic attacks, (c) thetreatment or prevention of any thrombotic syndrome occurring in thevenous system including deep venous thrombosis or pulmonary embolusoccurring either spontaneously or in the setting of malignancy, surgeryor trauma, (d) the treatment or prevention of any coagulopathy includingdisseminated intravascular coagulation (including the setting of septicshock or other infection, surgery, pregnancy, trauma or malignancy andwhether associated with multi-organ failure or not), thromboticthrombocytopenic purpura, thromboangiitis obliterans, or thromboticdisease associated with heparin induced thrombocytopenia, (e) thetreatment or prevention of thrombotic complications associated withextracorporeal circulation (e.g. renal dialysis, cardiopulmonary bypassor other oxygenation procedure, plasmapheresis), (f) the treatment orprevention of thrombotic complications associated with instrumentation(e.g. cardiac or other intravascular catheterization, intra-aorticballoon pump, coronary stent or cardiac valve), and (g) those involvedwith the fitting of prosthetic devices.

Anticoagulant therapy is also useful to prevent coagulation of storedwhole blood and to prevent coagulation in other biological samples fortesting or storage. Thus the compounds of this invention can be added toor contacted with any medium containing or suspected to contain factorXa and in which it is desired that blood coagulation be inhibited, e.g.,when contacting the mammal's blood with material such as vasculargrafts, stents, orthopedic prostheses, cardiac stents, valves andprostheses, extra corporeal circulation systems and the like.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds of the presentinvention and practice the claimed methods. The following workingexamples therefore, specifically point out preferred embodiments of thepresent invention, and are not to be construed as limiting in any waythe remainder of the disclosure.

EXAMPLES Example 1

Part 1. Into a chilled suspension of 4-amino-3-nitrobenzoic acid (3.6 g,20 mmol) in dry methanol (45 mL) was bubbled gaseous HCl for 10 min. Theyellow suspension was stirred at room temperature for 2 days. Thereaction mixture was filtered, washed with cold methanol and dried underhigh vacuum to give the HCl salt of methyl 4-amino-3-nitrobenzoate (3.25g, 70%) as a yellow solid.

Part 2. To a chilled suspension of methyl 4-amino-3-nitrobenzoate (2.56g, 11 mmol) and 4-dimethylaminopyridine (68 mg, 0.56 mmol) in CH₂Cl₂ (40mL) and N,N-diisopropyl-ethylamine (1.9 mL, 11 mmol) was added asolution of di-tert-butyldicarbonate (2.2 g, 10 mmol) in CH₂Cl₂ (20 mL)dropwise over 20 min. The suspension was stirred at room temperature for2 hours. Another solution of di-tert-butyldicarbonate (1.2 g, 5.5 mmol)in CH₂Cl₂ (10 mL) was added, and the resulting solution was stirred foranother hour. The reaction was then concentrated, diluted with ethylacetate, washed with 5% citric acid, water and brine, dried over sodiumsulfate and concentrated in vacuo. The residue was purified by silicagel chromatography using 5% ethyl acetate in CH₂Cl₂ as eluent to yieldmethyl 4-[(tert-butoxy)carbonylamino]-3-nitrobenzoate (2.4 g, 74%). ¹HNMR (CDCl₃) δ: 1.54 (s, 9H); 3.93 (s, 3H); 8.19-8.22 (d, 1H); 8.66-8.68(d, 1H); 8.86 (s, 1H); 9.87 (s, 1H).

Example 2

Part 1. To a solution of methyl4-[(tert-butoxy)carbonylamino]-3-nitrobenzoate (0.44 g, 1.5 mmol) inmethanol (2 mL), ethyl acetate (3 mL) and triethylamine (0.21 mL, 1.5mmol) was added 10% Pd on carbon (159 mg, 0.15 mmol). The reactionmixture was hydrogenated under 1 atm H₂ for 3.5 hours, filtered, andconcentrated in vacuo to yield methyl3-amino-4-[(tert-butoxycarbonyl)amino]benzoate (0.40 g, 99%) as a whitesolid. ES-MS (M+H—C₄H₈)⁺=211.1.

Part 2. To a chilled solution of methyl3-amino-4-[(tert-butoxy)carbonylamino]benzoate (0.40 g, 1.5 mmol) inCH₂Cl₂ (10 mL) and triethylamine (0.21 mL, 1.5 mmol) was added asolution of triphosgene (161 mg, 0.54 mmol) in CH₂Cl₂ (6 mL) over 5 min.The reaction was stirred at room temperature for 2 hr, diluted withCH₂Cl₂, washed with water and brine, dried over sodium sulfate andconcentrated in vacuo. The crude product was purified by silica gelchromatography using 50% ethyl acetate in CH₂Cl₂ as eluent to givemethyl1-[(tert-butyl)oxycarbonyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (0.27g, 61%).

¹H NMR (CDCl₃) δ: 1.68 (s, 9H); 3.91 (s, 3H); 7.73 (s, 1H); 7.79-7.81(d, 1H); 7.85-7.87 (dd, 1H); 8.9 (s, 1H). ES-MS (M+H—C₄H₈)⁺=237.1.

Example 3

Part 1. To a chilled solution of methyl1-[(tert-butyl)oxycarbonyl]-2-oxo-(3H)—benzimidazole-5-carboxylate (0.37g, 1.28 mmol) in CH₂Cl₂ (8 mL) and N,N-diisopropylethylamine (0.23 mL,1.3 mmol) was added a solution of benzyl chloroformate (0.208 mL, 1.46mmol) in CH₂Cl₂ (2 mL). The reaction was stirred at room temperature for2.5 hr, diluted with ethyl acetate, washed with water and brine, driedover sodium sulfate and concentrated in vacuo. This residue wasdissolved in CH₂Cl₂ (9 mL) and treated with neat trifluoroacetic acid (2mL) at 0° C. for 40 min, diluted with ethyl acetate, washed with 5%NaHCO₃, water and brine, dried over sodium sulfate and concentrated toyield methyl2-oxo-3-[benzyloxycarbonyl]-(3H)—benzimidazole-5-carboxylate (0.37 g,89%) as an off-white solid. ¹H NMR (CDCl₃) δ: 3.51 (s, 3H); 5.14 (s,2H); 6.67-6.69 (d, 1H); 6.97-7.06 (m, 5H); 7.17-7.18 (d, 1H); 7.51-7.53(d, 1H); 8.07 (s, 1H). ES-MS (M+Na)⁺=349.0.

Example 4

To a chilled solution of methyl2-oxo-3-(benzyloxycarbonyl)—(3H)—benzimidazole-5-carboxylate (110 mg,0.337 mmol) in DMF (3 mL) was added cesium carbonate (0.275 g, 0.84mmol) followed by 7-(bromomethyl)naphthalene-2-carbonitrile (108 mg,0.44 mmol). The reaction was stirred at room temperature for 1.5 hours,diluted with ethyl acetate, washed with water and brine, dried oversodium sulfate and concentrated in vacuo. This residue was redissolvedin methanol (4 mL), CH₃CN (3 mL) and IN LiOH (0.7 mL). The reactionmixture was stirred for 1 hour, acidified with 1N HCl (0.7 mL), filteredand dried to yield methyl1-[(7-cyano(2-naphthyl))methyl]-2-oxo-(3H)—benzimidazole-5-carboxylate(84 mg, 70%) as awhite solid. ES-MS (M+H)⁺=358.1.

To a suspension of methyl1-[(7-cyano-2-naphthyl)methyl]-2-oxo-(3H)—benzimidazole-5-carboxylate(82 mg, 0.23 mmol) in CH₃CN (2.5 mL) and methanol (2 mL) was added 1NLiOH (2.3 mL, 10 eq.). The reaction mixture was stirred at roomtemperature for 3 days, acidified with 1N HCl (2.4 mL), filtered anddried to yield1-[(7-cyano-2-naphthyl)methyl]-2-oxo-(3H)—benzimidazole-5-carboxylicacid (72 mg, 91%) as a white solid. ¹H NMR(CDCl₃) δ: 5.16 (s, 2H);6.77-6.79 (d, 1H); 7.50-7.54 (t, 2H); 7.62-7.64 (dd, 1H); 7.68 (s, 1H);7.72 (s, 1H); 7.78-7.84 (dd, 2H); 8.11 (s, 1H); 10.8 (s, 1H). ES-MS(M+H)⁺=344.1.

Example 5

A solution of1-[(7-cyano-2-naphthyl)methyl]-2-oxo-(3H)—benzimidazole-5-carboxylicacid (70 mg, 0.20 mmol) and hydroxylamine hydrochloride (28 mg, 0.40mmol) in dry ethanol (4 mL) and DIEA (0.11 mL, 0.61 mmol) was stirred at55° C. for 8 hours. The reaction was concentrated in vacuo, and theresulting residue redissolved in glacial acetic acid (4 mL). To thissolution was added acetic anhydride (0.038 mL, 0.40 mmol). The reactionmixture was stirred at room temperature for 1 hr, followed by additionof methanol (3 mL) and 10% Pd on carbon (24 mg, 0.023 mmol). The mixturewas hydrogenated under 1 atm H₂ for 17 hours, filtered, and concentratedin vacuo. Purification on a Vydac C₁₈ HPLC column yielded1-[(7-carboxamidino-2-naphthyl)methyl]-2-oxo-(3H)—benzimidazole-5-carboxylicacid (30 mg, 41%) as a white fluffy solid after lyophilization. ¹H NMR(DMSO-d₆) δ: 5.29 (s, 2H); 7.17-7.19 (d, 1H); 7.56 (s, 1H); etc. ES-MS(M+H)⁺=361.1.

Example 6

To a suspension of1-[(7-carboxamidino-2-naphthyl)methyl]-2-oxo-(3H)—benzimidazole-5-carboxylicacid (7 mg, 0.019 mmol) and BOP reagent (10 mg, 0.023 mmol) in DMF (0.8mL) and N,N-diisopropylethylamine (10 mL, 0.057 mmol) was added neatpyrrolidine (2 μL, 0.024 mmol). The resulting solution was stirred atroom temperature under argon for 4 hours. The reaction was concentratedand purified by HPLC to yield7-{[2-oxo-5-(pyrrolidinylcarbonyl)—(3H)—benzimidazolyl]methyl}naphthalene-2-carboxamidine(6 mg, 75%) as a white fluffy solid after lyophilization. ES-MS(M+H)⁺=414.1.

Example 7

Using a method similar method to that used in Example 6,1-[(7-carboxamidino-2-naphthyl))methyl]-2-oxo-(3H)-benzimidazole-5-carboxamidewas synthesized from the carboxylic acid via a BOP coupling withammonium hydroxide. ES-MS (M+H)⁺=360.1.

Example 8

Using a method similar to that used in Example 6,7-{[5-(N-methylcarbamoyl)-2-oxo-(3H)-benzimidazolyl]methyl}naphthalene-2-carboxamidinewas synthesized from the carboxylic acid via a BOP coupling withmethylamine. ES-MS (M+H)⁺=374.1.

Example 9

Using a method similar to that used in Example 6,7-{[5-(N,N-dimethylcarbamoyl)-2-oxo-(3H)-benzimidazolyl]methyl)naphthalene-2-carboxamidine was synthesized from the carboxylic acid viaa BOP coupling with dimethylamine. ES-MS (M+H)⁺=388.1.

Example 10

Using a method similar to that used in Example 6,3-{3-[2-oxo-5-(pyrrolidinylcarbonyl)-(3H)-benzimidazolyl]propoxy)benzamidine was synthesized by alkylation with3-(3-bromopropoxy)benzenecarbonitrile, saponification, BOP coupling withpyrrolidine, and hydroxylamine method for conversion of nitrile toamidine. ES-MS (M+H)⁺=408.1.

Example 11

Using a method similar to that used in Example 6,3-(2-methyl-5-{[2-oxo-5-(pyrrolidinylcarbonyl)-(3H)-benzimidazolyl)]methyl}-1,3-thiazol-4-yl)-benzamidinewas synthesized by alkylation with3-[5-(chloromethyl)-2-methyl-1,3-thiazol-4-yl]benzenecarbonitrile,saponification, BOP coupling with pyrrolidine, and hydroxylamine methodfor conversion of nitrile to amidine. ES-MS (M+H)⁺=461.0.

Example 12

Using a method similar to that used in Example 6,1-ethyl-2-{[2-oxo-5-(pyrrolidinyl-carbonyl)-(3H)-benzimidazolyl)]methyl}indole-6-carboxamidinewas synthesized by alkylation with2-(chloromethyl)-1-ethylindole-6-carbonitrile, saponification, BOPcoupling with pyrrolidine, and hydroxylamine method for conversion ofnitrile to amidine. ES-MS (M+H)⁺=431.1.

Example 13

Part 1. To a solution of 2H-1,4-Benzoxazin-3(4H)-one (1.86 g, 12.5 mmol,1.0 equiv) in 25 mL of CHCl₃ at 0° C. was added Br₂ (2.0 g, 1.0 equiv)dropwise. After stirring at room temperature overnight, the solvent wasevaporated and the residue was recrystallized from EtOH/H₂O to give theproduct in 95% yield. LRMS found for C₈H₇BrNO₂ (M+H)⁺: 227.9.

Part 2. A solution of the product from Part 1 (103 mg, 0.4 mmol, 1.0equiv), 2-(t-butylaminosulfonyl)phenylboronic acid (91.2 mg, 1.0 equiv),PdCl₂(dppf) (32.6 mg, 0.1 equiv), and triethylamine (279 μL, 5.0 equiv)in 10 mL of DME was degassed with argon for 15 min, then heated toreflux overnight. After cooling to room temperature, the mixture wasdiluted with ethyl acetate, washed with water, dried over MgSO₄, andconcentrated. Flash chromatography on silica gel gave the product in 21%yield. LRMS found for C₁₈H₂₁N₂O₄S (M+H)⁺: 361.1.

Part 3: A solution of the product from Part 2 (36 mg, 0.1 mmol, 1.0equiv) in 2 mL of DMF was treated with 2-bromomethyl-7-cyanonaphthalene(40 mg, 75%, 1.2 equiv) and Cs₂CO₃ 65 mg, 2 equiv) for 0.5 h. Themixture was diluted with ethyl acetate, washed with water and subjectedto flash column chromatography on silica gel to give the desired productin 95% yield. LRMS found for C₃₀H₂₈N₃O₄S (M+H)⁺: 526.2.

Step 4: The compound obtained in Step 3 (50 mg, 0.1 mmol, 1.0 equiv) wasdissolved in 5 mL of methanol. The reaction mixture was cooled to 0° C.and HCl gas was bubbled in until saturation, and the mixture was stirredat room temperature overnight. The solvent was evaporated and theresulting residue was treated with ammonium acetate and 10 ml ofmethanol at reflux temperature for 2 hr. The solvent was removed atreduced pressure and the crude benzamidine was purified by HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN to give the desiredsalt in 80% yield. LRMS found for C₂₆H₂₃N₄O₄S (M+H)⁺: 487.1.

Example 14

Step 1: The product from Example 13, Step 2 (36 mg, 0.1 mmol, 1.0 equiv)in 2 mL of DMF was treated with 2-bromomethyl-2′-cyanobiphenyl (41 mg,1.5 equiv) and Cs₂CO₃ (65 mg, 2 equiv) for 0.5 hr. The mixture wasdiluted with ethyl acetate, washed with water and purified by flashcolumn chromatography to give the desired product in 91% yield. LRMSfound for C₃₂H₃₀N₃O₄S (M+H)⁺: 552.2.

Step 2: The product from Step 1 (50 mg, 0.09 mmol, 1.0 equiv) wasdissolved in 5 mL of methanol. The reaction mixture was cooled to 0° C.,HCl gas was bubbled in until saturation, and the mixture was stirred atroom temperature overnight. The solvent was evaporated and the resultingresidue was treated with ammonium acetate and 10 ml methanol at refluxtemperature for 2 hr. The solvent was removed under reduced pressure andthe crude benzamidine was purified by HPLC (C18 reversed phase) elutingwith 0.5% TFA in H₂O/CH₃CN to give the desired salt in 77% yield. LRMSfound for C₂₈H₂₅N₄O₄S (M+H)⁺: 513.2.

Example 15 and 16

Part 1. A solution of 2-nitro-5-bromophenol (2.53 g, 18.2 mmol) in 15 mLof ethanol was treated with SnCl₂.H₂O, and the reaction was heated atreflux for 3 h. The solvent was evaporated to give a white residue,which was used in the next step without further purification. LRMS:C₉H₁₀NO₃ (M+H)⁺: 180.1.

Part 2. A solution of 2-amino-5-bromophenol (2.53 g, 18.2 mmol, 1.0equiv) in 15 mL of isobutylmethyl ketone and 15 mL of water was cooledto 0° C., NaHCO₃ (3.67 g, 2.4 equiv) and then chloroacetyl chloride(2.36 g, 1.67 mL, 1.15 equiv) were added. The mixture was heated toreflux overnight, then cooled to room temperature. The mixture wasdiluted with ethyl acetate, washed with water, dried over MgSO₄, andconcentrated in vacuo. Flash chromatography on silica gel gave7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one in 77% yield. LRMS found forC₉H₁₀NO₃ (M+H)⁺: 180.1.

Part 3. A solution of 7-bromo-3,4-dihydro-2H-1,4-benzoxazin-3-one (103mg, 0.4 mmol, 1.0 equiv), 2-t-butylaminosulfonyl phenyl boronic acid(91.2 mg, 1.0 equiv), PdCl₂(dppf) (32.6 mg, 0.1 equiv), andtriethylamine (279 μL, 5.0 equiv) in 10 mL of DME was degassed withargon for 15 min, then heated to reflux overnight. After cooling to roomtemperature, the mixture was diluted with ethyl acetate, washed withwater, dried over MgSO₄, evaporated. Flash chromatography on silica gelgave the product in 21% yield. LRMS found for C₁₈H₂₁N₂O₄S (M+H)⁺: 361.1.

Part 4. The product from Part 3 (36 mg, 0.1 mmol, 1.0 equiv) in 2 mL DMFwas treated with 1-(3-cyanophenyl)-3-methyl-5-chloromethyl pyrazole (35mg, 1.5 equiv) and Cs₂CO₃ (65 mg, 2 equiv) for 0.5 hr. The mixture wasdiluted with ethyl acetate, washed with water and purified over silicagel to give the desired product in 91% yield. LRMS found for C₃₀H₂₉N₅O₄S(M+H)⁺: 556.1.

Part 5. The compound from Part 4 (50 mg, 0.09 mmol, 1.0 equiv) wasdissolved in 5 mL of methanol. The reaction mixture was cooled to 0° C.,HCl gas was bubbled in until saturation, and the mixture was stirred atroom temperature overnight. The solvent was evaporated and the resultingresidue was treated with ammonium acetate and 10 ml of methanol atreflux temperature for 2 hr. The reaction was concentrated in vacuo andthe crude benzamidine was purified by HPLC (C18 reversed phase) elutingwith 0.5% TFA in H₂O/CH₃CN to give the desired amidine (Example 15) in77% yield. LRMS found for C₂₆H₂₄N₆O₄S (M+H)⁺: 516.2. Example 16 wasobtained as a byproduct in 15% yield. LRMS found for C₂₆H₂₃N₅O₅S (M+H)⁺:517.1.

Example 17

Part 1: The product (36 mg, 0.1 mmol, 1.0 equiv) obtained in Part 3 ofExample 15 in 2 mL DMF was treated with1-(3-cyanophenyl)-3-methyl-5-chloromethyl pyrazole (41 mg, 1.5 equiv)and Cs₂CO₃ 65 mg, 2 equiv) for 0.5 h. The mixture was diluted with ethylacetate, washed with water and purified over silica gel to give thedesired product in 91% yield. LRMS found for C₃₂H₃₀N₃O₄S (M+H)⁺: 552.2.

Part 2: The compound obtained in Part 1 (50 mg, 0.09 mmol, 1.0 equiv)was dissolved in 5 mL of methanol. The reaction mixture was cooled to 0°C., HCl gas was bubbled in until saturation, and the mixture was stirredat room temperature overnight. The solvent was evaporated and theresulting residue was treated with ammonium acetate and 10 ml ofmethanol at reflux temperature for 2 hr. The solvent was removed atreduced pressure and the crude benzamidine was purified by HPLC (C18reversed phase) eluting with 0.5% TFA in H₂O/CH₃CN to give the desiredsalt in 77% yield. LRMS found for C₂₈H₂₅N₄O₄S (M+H)⁺: 513.2.

Example 18

To a solution of tert-butylamine (41.4 g, 566 mmol) and triethylamine(118 mL, 849 mmol) in DCM (1000 mL) in an ice bath, was addedbenzenesulfonyl chloride (100 g, 566 mmol) dropwise, and the mixture wasstirred at room temperature overnight. Water was added to the mixtureand organic layer was washed with water, sat. NaCl, dried over Na₂SO₄,filtered and filtrate evaporated in vacuo to give the title compound aslight yellow solid (117.63 g, 97.6%). ES-MS (M+H)+=214.5.

Example 19

A solution of the compound from example 18 (53.25 g, 250 mmol) in THF(600 mL) was cooled with an ice water bath, and a 2.5 M solution ofn-butyllithium in hexane (200 mL, 500 mmol) was added dropwise. A thickprecipitate was formed when the reaction mixture was warmed up to 10° C.Triisopropylborate was added, keeping the temperature below 35° C. After1 hr., the mixture was cooled in an ice bath, 1N HCl (405 mL) was added,and the mixture was stirred overnight. The mixture was extracted withether (3×100 mL), and the combined organic extracts were extracted with1N NaOH (3×130 mL). The aqueous extracts were acidified to pH 1 with 12N HCl, and then extracted with ether (3×140 mL). The combined etherextracts were dried over MgSO₄, and solvents were evaporated in vacuo.Hexane and ether were added and a white precipitate formed. The solidwas collected and washed with 10% ether/hexane to give the titlecompound. ES-MS (M+H)+=b

Example 20

To a solution of 5-bromoindole (1.96 g, 10 mmol) in DME (40 mL) and H₂O(10 mL), was added the compound from Example 19 (3.85 g, 15 mmol),NaHCO₃ (1.68 g, 20 mmol) and tetrakis(triphenylphosphine)palladium(0)(0.58 g, 0.5 mmol). The mixture was heated to reflux overnight, thencooled to room temperature and diluted with ethyl acetate. The organiclayer was washed with water, dried with MgSO₄, filtered andconcentrated. The residue was purified by silica gel columnchromatography using 25% ethyl acetate in hexane as eluent to give thetitle compound (1.52 g, 46%). ES-MS (M+Na)⁺ 351.1.

Example 21

To a solution of the compound from Example 20 (328 mg, 1 mmol) in DMF(10 mL) was added 7-cyano-2-bromomethylnaphthalene (296 mg, 1.2 mmol)and Cs₂CO₃ (1.3 g, 4 mmol), and the mixture was stirred at roomtemperature overnight. The reaction mixture was partitioned betweenwater and ethyl acetate, and the organic layer was washed with water, 1NHCl, sat. NaCl, dried over Na₂SO₄ and concentrated in vacuo. The residuewas subjected to flash column chromatography on silica gel using 50%ethyl acetate in CH₂Cl₂ followed by 100% CH₂Cl₂ as eluent to give thetitle compound (237 mg, 48%). ES-MS (M+H)⁺=494.2.

Example 22

A solution of the compound from example 21 (115 mg, 0.23 mmol) in 20%MeOH/ethyl acetate (10 mL) was treated with a stream of HCl gas for 10min. at 0° C. The resulting solution was capped, stirred at roomtemperature overnight, then concentrated in vacuo.

The residue was reconstituted in MeOH (10 mL) and the mixture wastreated with ammonium acetate (350 mg, 4.6 mmol). The reaction mixturewas heated at reflux for 2 hrs, then concentrated in vacuo. The residuewas purified by prep HPLC to give the title compound as a white powder.ES-MS (M+H)⁺=511.2.

Example 23

Part 1. A solution of 4-bromo-2-nitroaniline (2.97 g, 13.7 mmol) in 100mL of dichloromethane was treated with N,N-diisopropylethylamine (2.38mL, 13.7 mmol) and 4-dimethylaminopyridine (167 mg, 1.37 mmol).Di-tert-butyldicarbonate (3.88 g, 17.8 mmol) was then added in smallportions. The mixture was stirred at room temperature overnight underargon, then diluted with 400 mL of dichloromethane and washed with water(×2). The organic phase was dried over MgSO₄, concentrated in vacuo andpurified by flash column chromatography. The desired product wasobtained as a yellow solid in 48% yield (2.07 g).

Part 2. To a mixture of the product from Part 1 (1.02 g, 3.22 mmol), theboronic acid from Example 19 (827 mg, 3.22 mmol), andtetrakis(triphenylphosphine)palladium(0) (186 mg, 0.161 mmol) in 60 mLof benzene was added a solution of sodium hydroxide (515 mg, 12.9 mmol)in 5 mL of water. The mixture was degassed using an argon stream for 15minutes and then heated at reflux for 24 hours. The solution wasconcentrated in vacuo, the residue was dissolved in ethyl acetate,passed through a bed of celite, and washed with water (×2). The organicphase was dried over MgSO₄, concentrated in vacuo, then purified byflash column chromatography. The desired product was obtained as a solidin 60% yield (0.87 g).

Part 3. The product from Part 2 (72 mg, 0.16 mmol) and the bromide fromExample 24 (80 mg, 0.24 mmol) were dissolved in 4 mL of dry DMF, andcesium carbonate (156 mg, 0.48 mmol) was added. The resulting mixturewas stirred overnight, then diluted with 100 mL of ethyl ether, washedwith water (×2), and dried over MgSO₄. Filtration and concentration invacuo gave a residue, which was subjected to flash columnchromatography. The desired product was obtained in 43% yield (48 mg).

Part 4. The product from Part 3 (90 mg, 0.13 mmol) was dissolved in 5 mLof ethyl alcohol, and tin(II) chloride dihydrate (116 mg, 0.52 mmol) wasadded. The mixture was heated to reflux for 3 hours, and the ethanol wasremoved in vacuo. The residue was dissolved in ethyl acetate, washedwith 1N aqueous NaOH and water. The organic phase was dried over MgSO₄,concentrated in vacuo and pumped to dryness to give the desired productin quantitative yield (84 mg).

Part 5. The crude product from Part 4 (84 mg) was dissolved in 7 mLglacial acetic acid, and the mixture was stirred at 80° C. overnight.The mixture was concentrated with toluene to remove traces of aceticacid, and the residue was purified by preparative HPLC.

Part 6. The product from Part 5 (20 mg, 0.034 mmol) was dissolved in 5mL anhydrous methanol, and a vacuum-distilling adapter, equipped with arubber septum and with a balloon on its side-arm, was placed on thereaction flask. The solution was chilled in ice, and HCl gas was bubbledthrough the solution via a long needle immersed in the solution untilthe balloon expanded, and this reaction mixture was stirred overnight.The reaction was concentrated to dryness in vacuo, then dissolved in 5mL of anhydrous methanol, and dry ammonium acetate (21 mg, 0.27 mmol)was added. The mixture was heated at reflux for 2 hours, then purifiedby preparative HPLC to afford the title compound. LRMS (M+H)⁺=553.

Example 24

Part 1. A mixture of 1,1,1-trifluoro-2,4-pentanedione (5.43 mL, 44.7mmol) and 3-bromophenylhydrazine HCl (10.0 g, 44.7 mmol) in 100 mL ofethanol was heated to reflux overnight. The reaction mixture wasconcentrated in vacuo, and the residue was dissolved in ethyl ether andwashed with water (×2). The organic phase was dried over MgSO₄,concentrated and subjected to flash column chromatography, giving 12.83g (94%) of the desired product as an oil, which was a mixture of the twopossible regioisomers.

Part 2. The mixture of isomers from part 1 (12.83 g, 41.9 mmol), KCN(5.45 g, 83.8 mmol), CuI (798 mg, 4.19 mmol) andtetrakis(triphenylphosphine)palladium(0) (2.42 g, 2.09 mmol) in 100 mLof acetonitrile was degassed using an argon stream for 30 minutes. Themixture was heated at reflux for 15 hours, then passed through a silicaplug on a Buchner funnel using ethyl acetate as eluent. The filtrate wasconcentrated and dissolved in dichloromethane, washed with water (×2),and dried over MgSO₄. Filtration and concentration gave a residue, whichwas subjected to column chromatography. The regioisomeric products wereseparable at this stage, giving 3.93 g (37%) of the 3-methyl and 4.0 g(38%) of the 5-methyl isomers.

Part 3. A mixture of the 5-methyl isomer (1.67 g, 6.63 mmol), NBS (1.41g, 7.95 mmol), and AIBN (543 mg, 3.31 mmol) in 50 mL carbontetrachloride was degassed using an argon stream for 15 minutes. Thereaction was heated at reflux for 2 days, periodically adding additionalsmall amounts of AIBN. The resulting mixture was diluted withdichloromethane, washed with water (×2), and dried over MgSO₄.Filtration and concentration gave a residue, which was subjected toflash column chromatography. The desired bromomethyl product wasobtained in 1.06 g (48%), along with 1.06 g of recovered startingmaterial.

Examples 25 and 26

Part 1. The nitro compound from Part 2 of Example 23 (2.70 g, 6.01 mmol)was dissolved in 60 mL of ethanol, and tin(II) chloride dihydrate (5.43g, 24.0 mmol) was added. The mixture was heated at reflux for 1 hour,then concentrated on the rotovap. The residue was washed through a plugof silica gel and concentrated to give another residue, which wasdissolved in 20 mL of formic acid (88%) and stirred at 55° C. for 1hour. Traces of formic acid were removed by evaporation with toluene invacuo, and the desired product was obtained by flash columnchromatography to give 516 mg (26%) of the desired benzimidazole. LRMS(M+H)⁺=330.

Part 2. The benzimidazole from Part 1 (62 mg, 0.188 mmol) was dissolvedin 5 mL of DMF, followed by the addition of2-bromomethyl-7-cyanonaphthalene (93 mg, 0.376 mmol) and cesiumcarbonate (184 mg, 0.564 mmol). The mixture was stirred overnight, thendiluted with ethyl acetate and washed with water (×2). The organic phasewas dried over MgSO₄, concentrated in vacuo, and the desired productswere obtained as a mixture of two regiosomers by flash columnchromatography.

Part 3. The mixture of isomers from Part 2 (90 mg, 0.18 mmol) wasdissolved in 10 mL of dry methanol. A vacuum-distilling adapter,equipped with a rubber septum and with a balloon on its side-arm, wasplaced on the reaction flask. The solution was chilled in ice, and HClgas was introduced via a long needle immersed in the solution until theballoon began to inflate. The mixture was stirred overnight and thenconcentrated to dryness in vacuo. The residue was dissolved in 5 mLanhydrous methanol, and dry ammonium acetate (139 mg, 1.8 mmol) wasadded. The mixture was heated at reflux for 2 hours, then purified bypreparative HPLC to afford the two title compounds. LRMS (M+H)⁺=457.

Example 27

Part 1. To a solution of 5-bromoindoline (1.0 g, 5 mmol) in 10 ml ofdioxane was added 5 mL of a 1N NaOH solution and 5 mL of water. Thismixture was cooled with an ice bath, and di-tert-butyl dicarbonate (1.2g, 5.5 mmol) was added in one portion. The reaction was allowed to warmto room temperature, stirred for 4 hours, and then concentrated. Theresidue was extracted with ethyl acetate (2×25 mL), and the combinedorganic phases were washed with water (2×25 mL), saturated aqueous NaCl(2×25 ml), then dried over MgSO₄. Filtration and concentration in vacuogave N-Boc-5-bromoindoline (1.33 g, 89%) as a light brown powder afterdrying. ¹H NMR (CDCl₃) δ: 1.541 (s, 9H); 3.03-3.08 (t, 2H); 3.92-3.96(t, 2H); 7.23-7.27 (m, 3H).

Part 2. To a solution of N-Boc-5-bromoindoline (104 mg, 0.35 mmol) in 5ml of anhydrous dioxane were added the boronic acid from Example 19 (100mg, 0.39 mmol), cesium carbonate (228 mg, 0.7 mmol) andtris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (10 mg, 0.01mmol). The reaction flask was thoroughly flushed with argon, andtri-tert-butylphosphine (0.006 mL, 0.025 mmol) was added via syringe.The reaction was heated to 80° C. and stirred overnight. The reactionwas then cooled to room temperature, diluted with 25 mL of diethylether, flushed through a pad of Celite and concentrated in vacuo to givea brown residue. This residue was subjected to flash columnchromatography on silica gel using 25% ethyl acetate in hexane to givethe desired biphenylamine (150 mg, 100%) as a light brown oil afterdrying. ¹H NMR (CDCl₃) δ: 1.02 (s, 9H); 1.22 (s, 9H); 3.10-3.15 (t, 2H);4.02, (t, 2H); 7.25-8.14 (m, 7H).

Part 3. The product from Part 2 was treated with 10 ml of 20%trifluoroacetic acid in dichloromethane for 10 minutes. The reactionmixture was concentrated in vacuo, redissolved in 25 mL ofdichloromethane, washed with 1N NaOH (2×25 ml), dried over magnesiumsulfate, filtered and concentrated in vacuo to give the desiredbiphenylamine as a brown oil after drying. ES-MS (M+H⁺): 330.5

Example 28

Part 1. 3-Cyano-4-fluoronitrobenzene (9.50 g, 57 mmol) was dissolved in250 mL of ethanol, 5% Pd/C (2.0 g) was added, and the black slurry wasstirred under a hydrogen balloon for 2 days. The reaction mixture wasfiltered through a celite bed and concentrated in vacuo to give theamino compound in 95% yield (7.37 g). LRMS (M+H)⁺ m/z 137. R_(f) 0.62(2:1 ethyl acetate/hexane).

Part 2. The amino compound from Part 1 (4.00 g, 29 mmol) was slurried in28 mL of conc. HCl and chilled in an ice bath. Sodium nitrite (2.00 g,29 mmol) was dissolved in 10 mL of water and chilled in ice bath, andthis solution was added dropwise to the cold slurry of the aminocompound. The reaction mixture was then stirred at 0° C. for 30 min. Tinchloride dihydrate (19.7 g, 29 mmol) was dissolved in 10 mL of conc. HCland chilled in ice bath, and this solution was added dropwise to theprevious reaction mixture. After completion, the mixture was chilled andthe solid hydrazine product was isolated by filtration through a Buchnerfunnel. This material was washed with cold brine (60 mL) and cold hexane(60 mL) to give 5.85 g of a yellow solid, which was used in the nextstep without further purification.

Part 3. Ethyl 2,4-dioxovalerate (20.0 g, 127 mmol) was dissolved in 100mL of ethanol, and methoxylamine hydrochloride (11.1 g, 133 mmol) wasadded. The mixture was heated at reflux for 20 hours, followed byconcentration of the reaction mixture in vacuo. The residue wasdissolved in ethyl acetate, and washed with water and brine. Theseparated organic phase was dried over MgSO₄ and evaporated in vacuo togive 19.3 g (81%) of the desired imine as an oil. LRMS (M+H)⁺ m/z 188.

Part 4. A solution of the product from Part 2 (5.85 g) and the productfrom Part 3 (3.80 g, 20.3 mmol) in acetic acid (100 mL) and THF (50 mL)was heated at reflux overnight, and the reaction mixture wasconcentrated in vacuo. The residue was taken up in ethyl acetate andwashed with water and brine. The organic phase was dried, filtered, andconcentrated and the residue was subjected to flash columnchromatography to yield the desired 5-carboethoxy isomer (4.45 g, 56%for two steps) and the undesired 3-carboethoxy isomer (1.00 g, 12% overtwo steps). LRMS (M+H)⁺ m/z 274. 5-Carbomethoxy isomer R_(f) 0.66 (1:1ethyl acetate/hexane). 3-Carbomethoxy isomer R_(f) 0.50 (1:1 ethylacetate/hexane).

Part 5. The biphenylamine from Example 27, Part 3 (90 mg, 0.27 mmol) wasdissolved in 2 mL of dichloromethane, and trimethylaluminum (0.7 mL of a2.0 M solution in hexane, 1.35 mmol) was added at room temperature. Themixture was stirred for 30 minutes, and then a solution of the5-carbomethoxy ester from Part 4 (77 mg, 0.28 mmol) in 3 mL ofdichloromethane was added dropwise to the reaction. The resultingmixture was stirred under argon overnight. The reaction was thenquenched by the careful addition of aqueous sat. Rocheile's salt, andthe reaction was extracted with dichloromethane (×3). The organic layerwas concentrated and the residue was subjected to flash columnchromatography to afford the desired coupling product (90 mg, 60%). LRMS(M+H)⁺ m/z 558. R_(f) 0.29 (1:1 ethyl acetate/hexane).

Part 6. The product from part 5 (83 mg, 0.15 mmol) was dissolved in 2 mLof ethanol, hydrazine monohydrate (40 μL, 0.75 mmol) was added dropwise,and the reaction mixture was heated at reflux overnight. Concentrationin vacuo gave a residue, which was dissolved in 2 mL of trifluoroaceticacid and heated at reflux for 30 minutes. The resulting mixture wasconcentrated and purified by prep HPLC [(C18 column, standard H₂O toCH₃CN gradient (0.1% TFA)] to give the desired compound. LRMS (M+H)⁺ m/z514.

Example 29

This compound was prepared from the 3-carbomethoxy intermediate fromPart 4 of Example 28 in a manner similar to that in Parts 4 and 5,Example 28.

Example 30

Part 1. 3-Bromophenylhydrazine hydrochloride (6.80 g, 30.4 mmol) and theproduct from Example 28, Part 3 (2.84 g, 15.2 mmol) were dissolved in 60mL of acetic acid and 30 mL of THF, and the reaction mixture was heatedat reflux overnight. The solvent was removed in vacuo, the residue wasdissolved in ethyl acetate, and the solution was washed with water andsat. NaCl. The organic layer was dried over MgSO₄, evaporated in vacuo,and purified by flash column chromatography to give the desired pyrazolein quantitative yield. LRMS (M+H)⁺ m/z 309, 311. R_(f) 0.47 (1:4 ethylacetate/hexane).

Part 2. The product from Part 1 was dissolved in 60 mL of acetonitrile,and KCN (2.91 g, 44.8 mmol), CuI (0.43 g, 2.2 mmol) and Pd(Ph₃P)₄ (1.3g, 1.1 mmol) were added. The mixture was degassed by bubbling argonthrough the solution for 30 minutes, and the reaction mixture was heatedunder argon at reflux overnight. The black mixture was then passedthrough a silica plug, and the filtrate was concentrated to give aresidue, which was taken up in ethyl acetate and washed with water (×2).The organic layer was dried, concentrated and subjected to flashchromatography to yield the desired nitrile as a white solid (2.69 g,10.5 mmol, 69% for two steps). LRMS (M+H)⁺ m/z 256. R_(f) 0.68 (1:1ethyl acetate/hexane).

Part 3. The product from Part 2 (2.00 g, 7.8 mmol) was dissolved in 40mL of methanol, and water (20 mL) and LiOH monohydrate (0.66 g, 15.7mmol) were added. The mixture was stirred for 1 hour, then acidifiedwith 5N HCl to a pH of 1. The methanol was removed in vacuo, and themixture was extracted with ethyl acetate (×3). The combined organicphases were dried and evaporated to give the desired acid as a whitesolid (1.38 g, 78%). LRMS (M+H)⁺ m/z 228, (M+Na)⁺ m/z 250.

Part 4. The acid from part 3 (200 mg, 0.88 mmol), the biphenyl aminefrom Example 25, Part 3 (290 mg, 0.88 mmol), and4,4-dimethylaminopyridine (10 mg) were dissolved in 4 mL of pyridine andchilled in ice bath. To the mixture was added POCl₃ (0.25 mL, 2.6 mmol),and the reaction was stirred in the cold for 1 hour. The reaction wasquenched with ice water, diluted with ethyl acetate, and the organicphase was washed with sat. NaCl (×2). The organic layer was dried,concentrated, and subjected to flash column chromatography to yield thedesired amide (240 mg, 51%). LRMS (M+H)⁺ m/z 540. R_(f) 0.37 (1:1 ethylacetate/hexane).

Part 5. The product from Part 4 (140 mg, 0.26 mmol) was dissolved in 10mL of anhydrous DMF and chilled in ice bath. To the reaction mixture wasadded NaBH4 (80 mg, 2.08 mmol) and anhydrous CoCl₂ beads (68 mg, 0.52mmol). The mixture was stirred for 30 minutes in the cold, then quenchedwith ice water and diluted with ethyl acetate. The mixture was filteredthrough a pad of celite, and the filtrate was washed with sat. NaCl(×2). The organic phase was dried, and concentrated in vacuo to give aresidue, which was dissolved in 2 mL of trifluoroacetic acid and stirredat 60° C. for 30 minutes. The mixture was purified by prep HPLC [(C18column, standard H₂O to CH₃CN gradient (0.1% TFA)] to afford the desiredaminomethyl compound. LRMS (M+H)⁺ m/z 488.

Examples 31 and 32

Part 1. A solution of the product from Example 27, Part 2 (80 mg, 0.2mmol) in 4 mL of CH₂Cl₂ was treated with 1 mL of trifluoroacetic acid,and the solution was stirred at room temperature for 10 min. Thereaction mixture was then concentrated, and again concentrated fromheptane to remove traces of trifluoroacetic acid. The residue wasdissolved in 5 mL of DMF, and the bromomethyl compound from Example 24,Part 3 (80 mg, 0.24 mmol) was added, together with 195 mg of cesiumcarbonate, and the solution was stirred at room temperature for 1 hr.The reaction was diluted with ethyl acetate (25 mL), washed with waterand sat. NaCl, and the organic layer was dried over MgSO₄. Filtrationand concentration gave a brown oil, which was used in the next reactionwithout further purification.

Part 2. The material from Part 1 (0.2 mmol) was taken up in 10 mL ofabsolute ethanol, and hydroxylamine hydrochloride (164 mg, 1.5 mmol) andtriethylamine (0.2 mL, 1.5 mmol) were added. The solution was heated to60° C. for 5 hours, then concentrated to give a residue, which was takenup in 5 mL of acetic acid, and acetic anhydride (0.2 mL) was added. Thereaction mixture was stirred at room temperature for 30 min, thenconcentrated to dryness, followed by concentration with heptane toremove traces of acetic acid. The residue was used in the next reactionwithout further purification.

Part 3. The crude product from Part 2 was taken up in 5 mL of absoluteethanol, 1 drop of acetic acid was added, followed by 10% Pd/C (5 mg),and the reaction was placed under a balloon of hydrogen. After 4 hours,the starting material was gone by HPLC, so the reaction mixture wasfiltered and subjected directly to preparative HPLC [C 18 column,standard H₂O to CH₃CN (0.1% TFA) gradient]. Two products were isolated,the expected indoline product, and a product where the indoline ring hadbeen oxidized to an indole ring. Indoline product: LRMS (M+H)⁺ m/z541.1. Indole product: LRMS (M+H)⁺ m/z 539.1.

Example 33

A solution of the product from Example 30, Part 4 (75 mg, 0.19 mmol) wastreated with methanol and HCl, followed by ammonium acetate in a mannersimilar to that in Example 23, Part 6. Preparative HPLC gave the desiredproduct.

Example 34

Treatment of the product from Example 30, Part 4 with hydroxylaminehydrochloride and triethylamine gave the above amidoxime.

Example 35

A solution of 4-bromoaniline (15 g, 87 mmol) and K₂CO₃ (181 g) in 170 mLof water was cooled to 5° C. A solution of cinnamoyl chloride (18.2 g,109 mmol) in acetone (87 mL) was added dropwise, resulting in theformation of a light brown solid. After 1 hour, the solid was recoveredby filtration, washed with cold water, once with cold ether and driedovernight at 80° C. at 20 mm Hg to give the desired product (23.8 g,90%). A portion of this amide (10 g, 33 mmol) was suspended inchlorobenzene (220 mL) and aluminum chloride (26 g, 195 mmol) was addedportionwise. The solution was heated at reflux for 2 hr, the solutionwas concentrated in vacuo to one half of its original volume, and thesolution was poured into 1L of ice water. The resulting solid wascollected by filtration and recrystallized from methanol to give6-bromoquinolin-2-one (5.0 g, 71%) as a brown solid.

Example 36

A solution of 6-bromohydroquinolin-2-one (1 g, 4.46 mmol),2-bromomethyl-7-napthonitrile (1.16 g, 4.46 mmol), and cesium carbonate(1.5 g, 5.35 mmol) in 15 mL of DMF was stirred at room temperature for18 h. The reaction mixture was diluted with water and ethyl acetate andfiltered through celite. The organic layer was washed with water (×2),then with sat. NaCl, dried over MgSO₄, and concentrated in vacuo. Theresidue was subjected to flash column chromatography on silica gel,using 100% CH₂Cl₂ as eluent to give7-[(6-bromo-2-oxohydroquinolyl)methyl]naphthalene-2-carbonitrile (876mg, 50%) as a white solid. ES-MS (M+H)⁺=389, 391.

Example 37

To a solution of7-[(6-bromo-2-oxohydroquinolyl)methyl]naphthalene-2-carbonitrile (30 mg,0.077 mmol), 2-{[(tert-butyl)amino]sulfonyl}phenylboronic acid (20 mg,0.077 mmol), Pd₂(dba)₃ (1 mg, 1.5 mol %), and cesium carbonate (25 mg,0.093 mmol) in dry dioxane (300 μL) was added tri-t-butylphosphine (0.7uL, 3.6 mol %). The reaction was heated to 75° C. for 11 h, cooled toroom temperature, and diluted with CH₂Cl₂ (2 mL). The solution was thenfiltered through celite, washed with 1N HCl and sat. NaCl, dried overMgSO₄, and concentrated in vacuo to afford7-{[6-(2-{[(tert-butyl)amino]sulfonyl}phenyl)-2-oxohydroquinolyl]methyl}naphthalene-2-carbonitrile(34 mg, 85%). ES-MS (M+H)+=522.2.

Example 38

A solution of the nitrile from Example 37 (34 mg, 0.64 mmol) in ethylacetate (5 mL) containing MeOH (150 μL) was cooled to −78° C. and HClgas was bubbled in until saturation. The solution was stirred whilewarming to room temperature over 18 h. The solvent was removed in vacuo,the residue was taken up in methanol (2 mL), and dried NH₄OAc (50 mg,0.64 mmol) was added. The mixture was heated to 80° C. for 1 h, cooled,and purified by preparative HPLC [(C18 column, water/CH₃CN gradient(0.1% TFA)]. The appropriate fractions were combined and lyophilized togive the desired amidine (5.6 mg, 19%) as a white powder. LRMS (M+H)⁺m/z 484.

Example 39

A solution of the nitrile from Example 37 (53 mg, 0.10 mmol) in methanol(0.5 mL) and DMF (0.25 mL) was treated with hydroxylamine hydrochloride(97 mg , 0.20 mmol), N,N-diisopropylethylamine (71 μL, 0.20 mmol). Thesolution was heated to 40° C. for 18 h, then concentrated in vacuo. Theresidue was stirred with TFA (2 mL) for 1 h, then concentrated in vacuo,and this residue was purified by preparative HPLC [(C18 column,water/CH₃CN gradient (0.1% TFA)]. The appropriate fractions werecombined and lyophilized to give the desired amidoxime (17 mg, 32%) as awhite powder. LRMS (M+H)⁺ m/z 499.

Example 40

Part 1. 7-Bromoisoquinoline

This compound was prepared as a 60:40 mixture with 5-bromoisoquinolineas in J. Am. Chem. Soc., 1939, 61, 183.

Part 2. 7-Bromoisoquinoline N-oxide Hydrochloride

This compound was prepared by a procedure analogous to that for6-bromoisoquinoline N-oxide hydrochloride as in PCT WO 98/47876. Asolution of 7.8 g (37.5 mmol) of a 60:40 mixture of 7-bromo and5-bromoisoquinoline in 125 mL of CH₂Cl₂ was treated portionwise with 9.7g (˜39.4 mmol) of 3-chloroperoxybenzoic acid (˜70% purity). Thesolution, which was initially homogeneous, deposited a voluminousprecipitate over 1 hr. Then 100 mL of methanol were added, and thereaction was concentrated to a volume of about 100 mL. Gaseous HCl wasthen bubbled through the solution for about 10 min, during which timethe solution became warm and all of the precipitate dissolved. A fewminutes later, another voluminous precipitate began to form. To thissolution was added 100 mL of ether, and the mixture was stirred in anice-water bath for 20 minutes. The resulting product was isolated byfiltration, washed thoroughly with ether, and air-dried to give 8.07 g(83%) of the desired compound as a white solid, which was still a 60:40mixture of the 7- and 5-bromo isomers.

Part 3. 7-Bromo-1-chloroisoquinoline

This compound was prepared by a procedure analogous to that for6-bromo-1-chloroisoquinoline as in PCT WO 98/47876. A solution of 8.07 g(31 mmol) of the mixture from Part B was taken up in 50 mL of POCl₃, andthe mixture was heated at 90° C. for 2 hr. The reaction mixture wasconcentrated to remove most of the POCl₃, and the residue was taken upin 100 mL of CH₂Cl₂. The solution was carefully basified to pH 10 by theslow addition of 1N NaOH, and the organic layer was washed with 100 mLof H₂O, 100 mL of sat. NaCl, and dried over MgSO₄. Filtration andconcentration gave a light yellow solid, which was subjected to flashcolumn chromatography on silica gel first with 5% and then with 10%ethyl acetate in hexanes. A total of 3.62 g (48%) of the desired7-bromo-1-chloroisoquinoline was isolated from this chromatography freeof the 5-bromo isomer.

Part 4. 7-Bromo-1-phenoxyisoquinoline

A solution of 3.60 g (14.8 mmol) of 7-bromo-1-chloroisoquinoline and 1.5g of solid KOH in 11.2 g of phenol was heated at 140° C. for 2 hr. Thereaction was cooled to room temperature, then partitioned between 100 mLof CH₂Cl₂ and 100 mL of 3N NaOH. The organic layer was washed withanother 2×100 mL of 3N NaOH, then with 100 mL of H₂O, and dried overMgSO₄. Filtration and concentration gave a yellow oil, which wassubjected to flash column chromatography on silica gel 30% CH₂Cl₂ inhexanes, giving 3.42 g (77%) of the desired product as a light yellowsolid.

Part 5. 1-Amino-7-bromoisoquinoline

A mixture of 3.40 g (11.3 mmol) of 1-amino-7-bromoisoquinoline and 7.65g of ammonium acetate was heated at 150° C. for 15 hr. The reaction wascooled, and the residue was partitioned between 200 mL of ethyl acetateand 200 mL of 3N NaOH. The organic layer was extracted with 2×100 mL of2N HCl, and the combined aqueous extracts were basified to pH 10 using50% NaOH. This solution was extracted with 2×100 mL of ethyl acetate,and the organics were then washed with 100 mL of sat. NaCl and driedover MgSO₄. Filtration and concentration gave 1.68 g (66%) of thedesired amino compound as a yellow solid.

Part 6. 1-[Bis(t-butoxycarbonyl)amino]-7-bromoisoquinoline

A solution of 740 mg (3.32 mmol) of 1-amino-7-bromoisoquinoline in 50 mLof acetonitrile was treated with 1.4 mL of N,N-diiospropylethylamine and100 mg of 4-(N,N-dimethylamino)pyridine, followed by 3.0 g (4.1 eq) ofdi-t-butyldicarbonate, and the reaction was stirred at 40° C. for 1 hr.By HPLC analysis, there was still some starting amino compound thatremained, so another 1.0 g of di-t-butyldicarbonate were added, and thereaction was stirred at 40° C. for another 30 min. The reaction mixturewas concentrated to give a dark oil, which was subjected to flash columnchromatography on silica gel with 20% ethyl acetate in hexanes to give736 mg of the desired product as a light yellow solid. Also isolatedwere 156 mg of product as a somewhat less pure fight yellow solid,making the total yield 64%.

Part 7. 1-[Bis(t-butoxycarbonyl)amino]isoquinoline-7-carboxaldehyde

A solution of 400 mg (0.95 mmol) of1-[bis(t-butoxycarbonyl)amino]-7-bromoisoquinoline in 50 mL of anhydrousTHF was cooled with a liquid nitrogen/methanol slush bath (−98° C.), and0.55 mL of a 2.43 M solution of n-BuLi in hexanes (1.3 eq) was addeddropwise over 1 min. The solution was stirred in the cold for 5 min,then a solution of 5 mL of anhydrous DMF in 10 mL of anhydrous THF wasadded rapidly. The solution was allowed to warm to about 0° C., thenpoured into 50 mL of 0.5 N HCl, and 50 mL of ethyl acetate were added.The aqueous layer was brought to pH 6 with 1N NaOH, 25 mL of sat. NaClwere added, and the layers were shaken and separated. The organic layerwas dried over MgSO₄, filtered, and concentrated to give an oilyresidue. This residue was subjected to flash column chromatography onsilica gel with 20% ethyl acetate in hexanes to give 190 mg (54%) of thedesired aldehyde as a yellow semisolid.

Part 8. (2Z)-3-{[1-bis(t-butoxycarbonyl)amino]isoquinolin-7-yl}acrylicAcid, 2-(Trimethylsilyl)ethyl Ester

A solution of 117 mg (0.29 mmol) of[bis(2,2,2-trifluoroethoxy)phosphinyl]acetic acid,2-(trimethylsilyl)ethyl ester (J. Org. Chem., 1991, 56, 4204) and 400 mgof 18-crown-6 in 25 mL of anhydrous THF was cooled with a dryice-acetone bath under argon, and 0.75 mL of a 0.5 M solution ofpotassium bis(trimethylsilyl)amide in toluene were added dropwise over 2min. The reaction was stirred in the cold for 15 min, then a solution of100 mg (0.27 mmol) of1-[bis(t-butoxycarbonyl)amino]isoquinoline-7-carboxaldehyde in 25 mL ofanhydrous THF was added dropwise over 10 min. The reaction was thenallowed to warm to room temperature overnight, then partitioned between100 mL of CH₂Cl₂ and 50 mL of H₂O. The organics were washed with aqueousNaCl, and dried over MgSO₄. Filtration and concentration gave an oilyresidue, which was subjected to flash column chromatography on silicagel with 25% ethyl acetate in hexanes to give 33 mg of the desiredproduct as a clear, colorless oil.

Part 9.(2Z)-N-[5-(2{[(N-1,1-dimethylethyl)amino]sulfonyl}phenyl)-1-indolinyl]-3-{[1-bis(t-butoxycarbonyl)amino]isoquinolin-7-yl}acrylamide

A solution of 498 mg (0.97 mmol) of(2Z)-3-{[1-bis(t-butoxycarbonyl)amino]isoquinolin-7-yl}acrylic acid,2-(trimethylsilyl)ethyl ester in 5 mL of DMF was treated at roomtemperature with 1.2 mL (1.25 eq) of a 1.0 M tetrabutylammonium fluoridein THF, and the reaction was stirred for 5 hr. The reaction mixture wasdiluted with 100 mL of ether, and the solution was washed with 100 mL ofwater. The aqueous layer was again extracted with 100 mL of ether, andthe combined organic layers were dried over Na₂SO₄. Filtration andconcentration gave 350 mg of an off-white solid, which was used withoutfurther purification. A solution of 50 mg of this carboxylic acid and 44mg of 2-indolin-5-ylbenzenesulfonamide from Example 27, Part 3 in 3 mLof DMF was treated with 100 μL of N,N-diisopropylethylamine and 60 mg ofHATU, and the reaction was stirred at room temperature overnight. Thereaction mixture was diluted with 100 mL of ethyl acetate and washedwith sat. NaHCO₃ (2×25 mL), and the organic layer was dried over MgSO₄.Filtration and concentration gave an orange oil, which was subjected toflash column chromatography on silica gel, using 20% ethyl acetate inhexanes as eluent to give 62 mg of the desired product as a yellow oil.

Part 10.(2Z)-N-[4-(2{aminosulfonyl}phenyl)-1-indolinyl]-3-{aminoisoquinolin-7-yl}acrylamide

A solution of the yellow oil from Part 9 in 2 mL of trifluoroacetic acidwas stirred at room temperature overnight. The reaction mixture wasconcentrated with CH₂Cl₂ to remove most of the TFA, then purifieddirectly by prep HPLC to give 15 mg of the desired product was obtainedas an off-white solid. LRMS (M +H)⁺=470.

Example 41

This compound was prepared by a method similar to that used in Example23, Part 6.

Example 42

This compound was prepared by a method similar to that used in Example23, Part 6.

Example 43

This compound was prepared by catalytic hydrogenation of the compoundfrom Example 42.

BIOLOGICAL ACTIVITY EXAMPLES

Evaluation of the compounds of this invention is guided by in vitroprotease activity assays (see below) and in vivo studies to evaluateantithrombotic efficacy, and effects on hemostasis and hematologicalparameters.

The compounds of the present invention are dissolved in buffer to givesolutions containing concentrations such that assay concentrations rangefrom 0 to 100 μM. In the assays for thrombin, prothrombinase and factorXa, a synthetic chromogenic substrate is added to a solution containingtest compound and the enzyme of interest and the residual catalyticactivity of that enzyme is determined spectrophotometrically. The IC₅₀of a compound is determined from the substrate turnover. The IC₅₀ is theconcentration of test compound giving 50% inhibition of the substrateturnover. The compounds of the present invention desirably have an IC₅₀of less than 500 nM in the factor Xa assay, preferably less than 200 nM,and more preferred compounds have an IC₅₀ of about 100 nM or less in thefactor Xa assay. The compounds of the present invention desirably havean IC₅₀ of less than 4.0 μM in the prothrombinase assay, preferably lessthan 200 nM, and more preferred compounds have an IC₅₀ of about 10 nM orless in the prothrombinase assay. The compounds of the present inventiondesirably have an IC₅₀ of greater than 1.0 μM in the thrombin assay,preferably greater than 10.0 μM, and more preferred compounds have anIC₅₀ of greater than 100.0 μM in the thrombin assay.

Amidolytic Assays for Determining Protease Inhibition Activity

The factor Xa and thrombin assays are performed at room temperature, in0.02 M Tris.HCl buffer, pH 7.5, containing 0.15 M NaCl. The rates ofhydrolysis of the paranitroanilide substrate S-2765 (Chromogenix) forfactor Xa, and the substrate Chromozym TH (Boehringer Mannheim) forthrombin following preincubation of the enzyme with inhibitor for 5minutes at room temperature, and were determined using the Softmax96-well plate reader (Molecular Devices), monitored at 405 nm to measurethe time dependent appearance of p-nitroaniline.

The prothrombinase inhibition assay is performed in a plasma free systemwith modifications to the method described by Sinha, U. et al., Thromb.Res., 75, 427-436 (1994). Specifically, the activity of theprothrombinase complex is determined by measuring the time course ofthrombin generation using the p-nitroanilide substrate Chromozym TH. Theassay consists of preincubation (5 minutes) of selected compounds to betested as inhibitors with the complex formed from factor Xa (0.5 nM),factor Va (2 nM), phosphatidyl serine:phosphatidyl choline (25:75, 20μM) in 20 mM Tris.HCl buffer, pH 7.5, containing 0.15 M NaCl, 5 mM CaCl₂and 0.1% bovine serum albumin. Aliquots from the complex-inhibitormixture are added to prothrombin (1 nM) and Chromozym TH (0.1 mM). Therate of substrate cleavage is monitored at 405 nm for two minutes. Eightdifferent concentrations of inhibitor are assayed in duplicate. Astandard curve of thrombin generation by an equivalent amount ofuntreated complex are used for determination of percent inhibition.

Antithrombotic Efficacy in a Rabbit Model of Venous Thrombosis

A rabbit deep vein thrombosis model as described by Hollenbach, S. etal., Thromb. Haemost. 71, 357-362 (1994), is used to determine thein-vivo antithrombotic activity of the test compounds. Rabbits areanesthetized with I.M. injections of Ketamine, Xylazine, andAcepromazine cocktail. A standardized protocol consists of insertion ofa thrombogenic cotton thread and copper wire apparatus into theabdominal vena cava of the anesthetized rabbit. A non-occlusive thrombusis allowed to develop in the central venous circulation and inhibitionof thrombus growth is used as a measure of the antithrombotic activityof the studied compounds. Test agents or control saline are administeredthrough a marginal ear vein catheter. A femoral vein catheter is usedfor blood sampling prior to and during steady state infusion of testcompound. Initiation of thrombus formation begins immediately afteradvancement of the cotton thread apparatus into the central venouscirculation. Test compounds are administered from time=30 min totime=150 min at which the experiment is terminated. The rabbits areeuthanized and the thrombus excised by surgical dissection andcharacterized by weight and histology. Blood samples are analyzed forchanges in hematological and coagulation parameters.

Effects of Compounds in Rabbit Venous Thrombosis Model

Administration of compounds in the rabbit venous thrombosis modeldemonstrates antithrombotic efficacy at the higher doses evaluated.There are no significant effects of the compound on the aPTT and PTprolongation with the highest dose (100 μg/kg+2.57 μg/kg/min). Compoundshave no significant effects on hematological parameters as compared tosaline controls. All measurements are an average of all samples aftersteady state administration of vehicle or (D)-Arg-Gly-Arg-thiazole.Values are expressed as mean ± SD.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the followingillustrative examples, make and utilize the compounds of the presentinvention and practice the claimed methods.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are described.

It should be understood that the foregoing discussion and examplesmerely present a detailed description of certain preferred embodiments.It will be apparent to those of ordinary skill in the art that variousmodifications and equivalents can be made without departing from thespirit and scope of the invention. All the patents, journal articles andother documents discussed or cited above are herein incorporated byreference. Briefer NOTE: All claims moved to end of this section of thepatent

The claimed invention is:
 1. A compound according to the formula:

wherein: A is selected from the group consisting of: (a) C₁-C₆-alkyl;(b) C₃-C₈-cycloalkyl; —N(—R²,—R³—C(═N—R²)—, (—R², —R³)N—C(═N—R²)—(—R²,—R³)N—C(═N—R²)—N(—R—)— (d) phenyl, which is independently substitutedwith 0-2 R¹ substituents; (e) naphthyl, which is independentlysubstituted with 0-2 R¹ substituents; and (f) a monocyclic or fusedbicyclic heterocyclic ring system having from 5 to 10 ring atoms,wherein 1-4 ring atoms of the ring system are selected from the groupconsisting of N, O and S, and wherein the ring system may be substitutedwith 0-2 R¹ substituents; R¹ is selected from the group consisting of:Halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, R²—C(═N—R³)—, (—R², —R³)N—C(═N—R²)—,—(CH₂)_(m)NR²R³, —C(═O)—N(—R², —R³), —SO₂N(—R², —R³), —SO₂R², —CF₃,—OR², and a 5-6 membered aromatic heterocyclic system containing from1-4 heteroatoms selected from the group consisting of N, O and S,wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system maybe independently replaced with a member selected from the groupconsisting of halo, C₁-C₄-alkyl, —CN C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂; R² and R³are independently selected from the group consisting of: H, —OR²,—N(—R², —R³), —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₄alkylC₃₋₈cycloalkyl, —C₀₋₄alkylphenyl and —C₀₋₄alkylnaphthyl,wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl andnaphthyl moieties may be independently replaced with a member selectedfrom the group consisting of halo, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂;or R² and R³ taken together can form a 3-8 membered cycloalkyl or aheterocyclic ring system, wherein the heterocyclic ring system may havefrom 5 to 10 ring atoms, with 1 to 2 rings being in the ring system andcontain from 1-4 heteroatoms selected from the group consisting of N, Oand S, wherein from 1-4 hydrogen atoms on the heterocyclic ring systemmay be independently replaced with a member selected from the groupconsisting of halo, C₁-C₄—alkyl, —CN—C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂; m isan integer of 0-2; Q is a member selected from the group consisting of:a direct link, —CH2—, —C(═O)—, —N(R⁴)—, —N(R⁴)CH2—, —C═N(R4)—,—C(═O)—N(R⁴)—, —N(R⁴)—C(═O)—, —SO₂—, —O—, —SO₂—N(R⁴)— and —N(R⁴)—SO₂—;R⁴ is selected from the group consisting of: H, —C₁₋₄alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl,—C₀₋₄alkylphenyl and —C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atomson the ring atoms of the phenyl and naphthyl moieties may beindependently replaced with a member selected from the group consistingof halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; D is a phenyl, which isindependently substituted with 0-2 R^(1a) substituents; R^(1a) isselected from the group consisting of: Halo, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂,(CH₂)_(m)NR^(2a)R^(3a), SO₂NR^(2a)R^(3a), SO₂R^(2a), CF₃, OR^(2a), and a5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O and S, whereinfrom 1-4 hydrogen atoms on the aromatic heterocyclic system may beindependently replaced with a member selected from the group consistingof halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂; R^(2a) and R^(3a) areindependently selected from the group consisting of: H, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl,C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atomson the ring atoms of the phenyl and naphthyl moieties may beindependently replaced with a member selected from the group consistingof halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂; M is a member selected from thegroup consisting of: —C(—R¹⁷,—R¹⁸)—C(═O)—,—C(—R¹⁷,—R^(17a))—C(—R¹⁸,—R^(18a))—, —C(—R¹⁷)═C(—R¹⁸)—, —C(═O)—C(═O)—and—C(═C(R^(17b), —R^(17c)))—C(═O)—, wherein the first named atom of thechain is directly attached to D, and wherein D, M and the N atomattached to the last chain atom of M collectively form a bicyclic ringstructure; R¹⁷, R^(17a), R¹⁸ and R^(18a) are each independently selectedfrom the group consisting of: hydrogen, halo, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂,(CH₂)_(m)NR²R³, SO₂NR²R³, SO₂R², CF₃, OR² , and a 5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O and S, wherein from 1-4 hydrogen atoms on thearomatic heterocyclic system may be independently replaced with a memberselected from the group consisting of halo, C₁-C₄-alkyl, —CN, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl and—NO₂; R^(17b) and R^(17c) are each independently a member selected fromthe group consisting of: hydrogen, —halo, hydroxy, —C₁₋₄alkyl,C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkyl—C₃₋₈cycloalkyl,—CN, —NO₂, —(CH₂)_(m)NR²R³, —SO₂NR²R³, —SO₂R², —CF₃, —OR², phenyl, and a5-6 membered aromatic heterocyclic ring containing from 1-4 heteroatomsselected from the group consisting of N, O and S, wherein from 1-4hydrogen atoms on the cycloalkyl, the phenyl ring, or the aromaticheterocyclic ring may be independently replaced with a member selectedfrom the group consisting of halo, C₁-C₄-alkyl, —CN, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl and—NO₂; E is a member selected from the group consisting of: a directlink, —C(═O)—, —C(═O)—N(R⁵)—, —C(—R^(5a),—R^(6a))— and—C(—R^(5b),—R^(6b))—C(—R^(5c),—R^(6c))—; wherein R⁵, R^(5a), R^(6a),R^(5b), R^(6b), R^(5c) and R^(6c) are independently selected from thegroup consisting of: p2 H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, C₀₋₄alkylheteroaryl, C₁₋₄alkylCOOH andC₁₋₄alkylCOOC₁₋₄alkyl, wherein from 0-4 hydrogen atoms on the ring atomsof the phenyl, naphthyl and heteroaryl moieties may be independentlyreplaced with a member selected from the group consisting of halo,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —OH, —O—C₁₋₄alkyl, —SH, —S—C₁₋₄alkyl, —CN and—NO₂; G is selected from the group consisting of: a direct link,—C(R⁷,R⁸)—, —C(R^(7a),R^(8a))—C(R^(7b),R^(8b))— and—C(R^(7c))═C(R^(8c))—; wherein R⁷, R⁸, R^(7a), R^(8a), R^(7b), R^(8b),R^(7c) and R8 c are independently a member selected from the groupconsisting of: hydrogen, halogen, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkyl —C₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, —OR⁹, —N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹,—C₀₋₄alkylC(═O)NR⁹R¹⁰, —C₀₋₄alkylC(═O)OR⁹,—C₀₋₄alkylC(═O)NR⁹—CH₂—CH_(2—O—R) ¹⁰,—C₀₋₄alkylC(═O)NR⁹(—CH₂—CH₂—O—R¹⁰—)₂, —N(R⁹)COR¹⁰,—N(R⁹)C(═O)R¹⁰,—N(R⁹)SO₂R¹⁰, a naturally occurring or synthetic aminoacid side chain, and C₀₋₄alkylheterocyclic ring having from 1 to 4hetero ring atoms selected from the group consisting of N, O and S,CH₂COOC₁₋₄alkyl, CH₂COOC₁₋₄alkylphenyl and CH₂COOC₁₋₄alkylnaphthyl,wherein from 1-4 hydrogen atoms on the CO₀₋₄alkylheterocyclic ring maybe independently replaced with a member selected from the groupconsisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂; wherein from 1-4 hydrogen atomson the ring atoms of the phenyl and naphthyl moieties may beindependently replaced with a member selected from the group consistingof halo, —OR⁹, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkyl—C₃₋₈cycloalkyl, —CN and —NO₂; R⁹ and R¹⁰ are independentlyselected from the group consisting of: H, C₁₋₄alkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, C₃₋₈cycloalkyl, and C₁₋₄alkyl—O—C₁₋₄alkyl,C₁₋₄alkyl—COOH wherein from 1-4 hydrogen atoms on the ring atoms of thephenyl and naphthyl moieties may be independently replaced with a memberselected from the group consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkyl—C₃₋₈cycloalkyl, —CN and —NO₂, andwherein R⁹ and R¹⁰ taken together can form a 5-8 membered heterocylicring; J is a member selected from the group consisting of: a directlink, —O—, —O—C(—R¹¹, —R^(11a))—, —S—, —S(═O)—, —S(═O)₂—, —S—C(—R¹¹,—R^(11a))—, —S(═O)—C(—R¹¹, —R^(11a))—, —S(═O)₂—(—R¹¹, —R^(11a))—,—C(═O)—, —C(═O)—N(R^(11b))—, —N(R^(11b))—C(═O)—, —N(R^(11b))—,—N(R^(11b))—C(—R¹¹, —R^(11a))— O and a monocyclic aromatic ornon-aromatic heterocyclic ring having from 5 to 8 ring atoms, wherein1-4 ring atoms of the ring system are selected from the group consistingof N, O and S, and wherein the ring system may be substituted with 0-2R¹¹ substituents; R¹¹, R^(11a), R^(11b), and R¹¹ are a memberindependently selected from the group consisting of: hydrogen, halo,—CF₃, —CN, —NR⁹R¹⁰, —SO₂Me, —NO₂, —OH, —O—C₁₋₄alkyl, —O—C₂₋₆alkenyl,—O—C—₂₋₆alkynyl, —O—C₃₋₈cycloalkyl, —O—C₁₋₄alkyl, —O—C₁₋₄alkyl,—O—C₁₋₄alkyl—COOH, —O—C₁₋₄alkyl-phenyl, —COOH, —C(═O)—O—C₁₋₄alkyl,—C(═O)—O—C₂₋₆alkenyl, —C(═O)—O—C₂₋₆alkynyl, —C(═O)—O—C₃₋₈cycloalkyl,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkyl—C₃₋₈cycloalkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl,C₀₋₄alkylC(═O)NR⁹R¹⁰, C₀₋₄alkylC(═O)OR⁹, C₀₋₄alkylheterocyclic ringhaving from 1 to 4 hetero ring atoms selected from the group consistingof N, O and S, CH₂COOC₁₋₄alkyl, CH₂COOC₁₋₄alkylphenyl andCH₂COOC₁₋₄alkylnaphthyl; wherein from 1-4 hydrogen atoms on theC₀₋₄alkylheterocyclic ring may be independently replaced with a memberselected from the group consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkyl-phenyl, C₀₋₄alkylC₃₋₈cycloalkyl,—CN and —NO₂; wherein from 1-4 hydrogen atoms on the ring atoms of thephenyl and naphthyl moieties may be independently replaced with a memberselected from the group consisting of halo, —OR⁹, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkyl—C₃₋₈cycloalkyl, —CNand —NO₂; Y is a member selected from the group consisting of: (a)phenyl, which is independently substituted with 0-2 R^(1b) substituents;(b) naphthyl, which is independently substituted with 0-2 R^(1b)substituents; and (c) a monocyclic or fused bicyclic heterocyclic ringsystem having from 5 to 10 ring atoms, wherein 1-4 ring atoms of thering system are selected from the group consisting of N, O and S, andwherein the ring system may be substituted with 0-2 R^(1b) substituents;R^(1b) is a member selected from the group consisting of: halo,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, NR^(2b)R^(3b), SO₂NR^(2b)R^(3b),SO₂R^(2b), CF₃, OR^(2b), O—CH₂—CH₂—OR^(2b), O—CH₂—COOR^(2b),N(R^(2b))—CH₂—CH₂—OR^(2b), N(—CH₂—CH₂—OR^(2b))₂, N(R^(2b))—C(═O)R^(3b),N(R^(2b))—SO₂—R^(3b), and a 5-6 membered aromatic heterocyclic systemcontaining from 1-4 heteroatoms selected from the group consisting of N,O and S, wherein from 1-4 hydrogen atoms on the aromatic heterocyclicsystem may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkyl-phenyl, —CN and —NO₂;R^(2b) and R^(3b) are independently selected from the group consistingof: H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, —OR⁹, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂; L is selectedfrom the group consisting of: H, —CN, C(═O)NR¹²R¹³, —(CH₂)_(n)NR¹²R¹³,C(═NR¹²) NR¹²R¹³, OR¹², —NR¹²C(═NR¹²)NR¹²R¹³, and NR¹²C(═NR¹²)—R¹³; n isan integer from 0 to 8; R¹² and R¹³ are independently selected from thegroup consisting of: <hydrogen, —OR¹⁴, —NR¹⁴R¹⁵, C₁₋₄alkyl,C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, COOC₁₋₄alkyl, COO—C₀₋₄alkylphenyland COO—C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ringatoms of the phenyl and naphthyl moieties may be independently replacedwith a member selected from the group consisting of halo, —OH,—O—C₁₋₄alkyl, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; R¹⁴ and R¹⁵ are independentlyselected from the group consisting of: H, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyland C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atomsof the phenyl and naphthyl moieties may be independently replaced with amember selected from the group consisting of halo, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN,and —NO₂; and all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives thereof.
 2. a phramceutical compositionfor preventing or treating a condition in a mammal characterized byundesired thrombosis comprising a therapeutacally acceptable carrier anda therapeutically effective amount of a compound of cliam
 1. 3. A methodfor preventing or treating a condition in a mammal characterized byundesired thrombosis comprising administering to said mammal atherapeutically effective amount of a compound of claim
 1. 4. The methodof claim 3, wherein the condition is selected from the group consistingof: acute coronary syndrome, myocardial infarction, unstable angina,refractory angina, occlusive coronary thrombus occurringpost-thrombolytic therapy or post-coronary angioplasty, a thromboticallymediated cerebrovascular, syndrome, embolic stroke, thrombotic strroke,transent ischemic attacks, venous thrombosis, deep venous thrombosis,pulmonary embolus, coagulopathy, dissemination intravascularcoagulation, thrombotic thrombocytopenic purpura, thromboangiitisobliterans, thrombotic disease associated with heparin-inducedthrombocytopenia, thrombotic complications associated withextracorporeal circulation, thrombotic complications associated withinstrumentation such as cardiac or other intravascular catherization,intra-aortic ballon pump, coronary stent, or cardiac valve, andconditions required the fitting of prosthettic devices.
 5. A method forinhibiting the coagulation of biological samples, comprising theadministration of a compound of claim
 1. 6. A compound of claim 1,wherein: A is selected from the group consisting of: (a) C₁-C₆-alkyl;(b) C₃-C₈-cycloalkyl; (c) phenyl, which is independently substitutedwith 0-2 R¹ substituents; (d) naphthyl, which is independentlysubstituted with 0-2 R¹ substituents; and (e) a monocyclic or fusedbicyclic heterocyclic ring system having from 5 to 10 ring atoms,wherein 1-4 ring atoms of the ring system are selected from the groupconsisting of N, O and S, and wherein the ring system may be substitutedwith 0-2 R¹ substituents; R¹ is selected from the group consisting of:halo, —C₁₋₄alkyl, —C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl,—C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, —(CH₂)_(m)NR²R³, —SO₂NR²R³, —SO₂R²,—CF₃, —OR², and a 5-6 membered aromatic heterocyclic system containingfrom 1-4 heteroatoms selected from the group consisting of N, O and S,wherein from 1-4 hydrogen atoms on the aromatic heterocyclic system maybe independently replaced with a member selected from the groupconsisting of halo, —C₁-C₄-alkyl, —CN, —C₁₋₄alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkylC₃₋₈cycloalkyl and —NO₂; R² andR³ are independently selected from the group consisting of: H,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; m is an integerof 0-2; Q is a member selected from the group consisting of: a directlink, —C(═O)—, —N(R⁴)—, —C(═O)—N(R⁴)—, —N(R⁴)—C(═O)—, —SO₂—, —O—,—SO₂—N(R⁴)— and —N(R⁴)—SO₂—; R⁴ is selected from the group consistingof: H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; D is a phenyl,which is independently substituted with 0-2 R^(1a) substituents; R^(1a)is selected from the group consisting of: halo, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈, —CN, —NO₂,(CH₂)_(m)NR^(2a)R^(3a), SO₂NR^(2a)R^(3a), SO₂R^(2a), CF₃, OR^(2a), and a5‥6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O and S, whereinfrom 1-4 hydrogen atoms on the aromatic heterocyclic system may beindependently replaced with a member selected from the group consistingof halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂; R^(2a)and R^(3a)are independentlyselected from the group consisting of: H, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl C₀₋₄alkylphenyl andC₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atoms ofthe phenyl and naphthyl moieties may be independently replaced with amember selected from the group consisting of halo, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CNand —NO₂; M, D and N collectively form a bicyclic ring structureselected from the group consisting of:

 wherein 0 to 2 of the hydrogen atoms on the D portion of the bicyclicring may be replaced by R^(1a) substituents as defined above; R¹⁷,R^(17a), R¹⁸ and R^(18a) are each independently selected from the groupconsisting of: halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, (CH₂)_(m)NR²R³,SO₂NR²R³, SO₂R², CF₃, OR², and a 5-6 membered aromatic heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O and S, wherein from 1-4 hydrogen atoms on thearomatic heterocyclic system may be independently replaced with a memberselected from the group consisting of halo, C₁-C₄-alkyl, —CN, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl and—NO₂; R^(17b) and R^(17c) are each independently a member selected fromthe group consisting of: <hydrogen, —halo, hydroxy, —C₁₋₄alkyl,C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₈cycloalkyl, —C₀₋₄alkyl—C₃₋₈cycloalkyl,—CN, —NO₂, —(CH₂)_(m)NR²R³, —SO₂NR²R³, —SO₂R², —CF₃, —OR², phenyl, and a5-6 membered aromatic heterocyclic ring containing from 1-4 heteroatomsselected from the group consisting of N, O and S, wherein from 1-4hydrogen atoms on the cycloalkyl, the phenyl ring, or the aromaticheterocyclic ring may be independently replaced with a member selectedfrom the group consisting of halo, C₁-C₄-alkyl, —CN, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl and—NO₂; E is a member selected from the group consisting of: a directlink, —C(═O)—, —C(═O)—N(R⁵)—, —C(—R^(5a),—R^(6a))— and—(—C(—R^(5b),—R^(6b))—C(—R^(5c),—R^(6c))—; wherein R⁵, R^(5a), R^(6a),R^(5b) R^(6b), R^(5c) and R^(6c) are independently selected from thegroup consisting of: H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, C₀₋₄alkylheteroaryl, C₁₋₄alkylCOOH andC₁₋₄alkylCOOC₁₋₄alkyl, wherein from 0-4 hydrogen atoms on the ring atomsof the phenyl, naphthyl and heteroaryl moieties may be independentlyreplaced with a member selected from the group consisting of halo,C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —OH, —O—C₁₋₄alkyl, —SH, —S—C₁₋₄alkyl, —CN and—NO₂; G is selected from the group consisting of: a direct link,—C(R⁷,R⁸)—, —C(R^(7a),R^(8a))—C(R^(7b),R^(8b))— and—C(R^(7c))═C(R^(8c))—; wherein R⁷, R⁸, R^(7a), R^(8a), R^(7b), R^(8b),R^(7c) and R^(8c) are independently a member selected from the groupconsisting of: hydrogen, halogen, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkyl—C₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, —OR⁹, —N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹,—C₀₋₄alkylC(═O)NR⁹R¹⁰, —C₀₋₄alkylC(═O)NR⁹—CH₂—CH₂—O—R¹⁰,—C₀₋₄alkylC(═O)NR⁹(—CH₂—CH₂—O—R¹⁰—)₂, —N(R⁹)COR¹⁰, —N(R⁹)C(═O)R¹⁰,—N(R⁹)SO₂R¹⁰, and a naturally occurring or synthetic amino acid sidechain, wherein from 1-4 hydrogen atoms on the ring atoms of the phenyland naphthyl moieties may be independently replaced with a memberselected from the group consisting of halo, —OR⁹, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkyl—C₃₋₈cycloalkyl, —CNand —NO₂; R⁹ and R¹⁰ are independently selected from the groupconsisting of: H, C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl,wherein from 1-4 hydrogen atoms on the ring atoms of the phenyl andnaphthyl moieties may be independently replaced with a member selectedfrom the group consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkyl—C₃₋₈cycloalkyl, —CN and —NO₂, and wherein R⁹and R¹⁰ taken together can form a 5-8 membered heterocylic ring; J is amember selected from the group consisting of: a direct link, —O—,—O—C(—R¹¹, —R^(11a))—, —S—, —S(═O)—, —S(═O)₂—, —S—C(—R¹¹, —R^(11a))—,—S(═O)—C(—R¹¹, —R^(11a))—, —S(═O)₂—(—R¹¹, —R^(11a))—, —C(═O)—,—C(═O)—N(R^(11b))—, —N(R^(11b))—C(═O)—, —N(R^(11b))—,—N(R^(11b))—C(—R¹¹,—R^(11a))— and a monocyclic aromatic or non-aromaticheterocyclic ring having from 5 to 8 ring atoms, wherein 1-4 ring atomsof the ring system are selected from the group consisting of N, O and S,and wherein the ring system may be substituted with 0-2 R^(11c)substituents; R¹¹, R^(11a), R^(11b) and R^(11c) are a memberindependently selected from the group consisting of: hydrogen, halo,—CN, —NO₂, —OH, —O—C₁₋₄alkyl, —O—C₂₋₆alkenyl, —O—C₂₋₆alkynyl,—O—C₃₋₈cycloalkyl, —COOH, —C(═O)—O—C₁₋₄alkyl, —C(═O)—O—C₂₋₆alkenyl,—C(═O)—O—C₂₋₆alkynyl, —C(═O)—O—C₃₋₈cycloalkyl, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkenyl, C₃₋₈cycloalkyl, C₀₋₄alkyl—C₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, C₀₋₄alkylheterocyclic ring having from 1 to 4 heteroring atoms selected from the group consisting of N, O and S,CH₂COOC₁₋₄alkyl, CH₂COOC₁₋₄alkylphenyl and CH₂COOC₁₋₄alkylnaphthyl; Y isa member selected from the group consisting of: (a) phenyl, which isindependently substituted with 0-2 R^(1b) substituents; (b) naphthyl,which is independently substituted with 0-2 R^(1b) substituents; and (c)a monocyclic or fused bicyclic heterocyclic ring system having from 5 to10 ring atoms, wherein 1-4 ring atoms of the ring system are selectedfrom the group consisting of N, O and S, and wherein the ring system maybe substituted with 0-2 R^(1b) substituents; R^(1b) is a member selectedfrom the group consisting of: halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, NR^(2b)NR^(3b),SO₂NR^(2b)R^(3b), SO₂R^(2b), CF₃, OR^(2b), O—CH₂—CH₂—OR^(2b),O—CH₂—COOR^(2b), N(R^(2b))—CH₂—CH₂—OR^(2b), N(—CH₂—CH₂—OR^(2b))₂,N(R^(2b))—C(═O)R^(3b), N(R^(2b))—SO₂—R^(3b), and a 5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O and S, wherein from 1-4 hydrogen atoms on thearomatic heterocyclic system may be independently replaced with a memberselected from the group consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;R^(2b) and R^(3b) are independently selected from the group consistingof: H, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl, whereinfrom 1-4 hydrogen atoms on the ring atoms of the phenyl and naphthylmoieties may be independently replaced with a member selected from thegroup consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂; L is selectedfrom the group consisting of: H, —CN, C(═O)NR¹²R¹³, (CH₂)_(n)NR¹²R¹³,C(═NR¹²)NR¹²R¹³, OR¹², —NR¹²C(═NR¹²)NR¹²R¹³, and NR¹²C(═NR¹²)—R¹³; n isan integer from 0 to 8; R¹² and R¹³ are independently selected from thegroup consisting of: hydrogen, —OR¹⁴, —NR¹⁴R¹⁵, C₁₋₄alkyl,C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, COOC₁₋₄alkyl, COO—C₀₋₄alkylphenyland COO—C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ringatoms of the phenyl and naphthyl moieties may be independently replacedwith a member selected from the group consisting of halo, —OH,—O—C₁₋₄alkyl, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl,C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; R¹⁴ and R¹⁵ are independentlyselected from the group consisting of: H, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyland C₀₋₄alkylnaphthyl, wherein from 1-4 hydrogen atoms on the ring atomsof the phenyl and naphthyl moieties may be independently replaced with amember selected from the group consisting of halo, C₁₋₄alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN,and —NO₂; and all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives thereof.
 7. A pharmaceuticalcomposition for preventing or treating a condition in a mammalcharacterized by undesired thrombosis comprising a therapeuticallyacceptable carrier and a therapeutically effective amount of a compoundof claim
 6. 8. A method for preventing or treating a condition in amammal characterized by undesired thrombosis comprising administering tosaid mammal a therapeutically effective amount of a compound of claim 6.9. The method of claim 8, wherein the condition is selected from thegroup consisting of: acute coronary syndrome, myocardial infarction,unstable angina, refractory angina, occlusive coronary thrombusoccurring pos-thrombolytic therapy or post-coronary angioplasty, athrombotically mediated cerebrovascular syndrome, embolic stroke,thrombotic stroke, transient ischemic attacks, venous thrombosis, deepvenous thrombosis, pulmonary embolus, coagulopathy, disseminatedintravascular coagulation, thrombotic thrombocytopenic purpura,thromboangiitis obliterans, thrombotic disease associated withheparin-induced thrombocytopenia, thrombotic complications associatedwith extracorporeal circulation, thrombotic complications associatedwith instrumentation such as cardiac or other intravascularcatheterization, intra-aortic balloon pump, coronary stent or cardiacvalve, and conditions requiring the fitting of prosthetic devices.
 10. Amethod for inhibiting the coagulation of biological samples, comprisingthe administration of a compound of claim
 6. 11. A compound of claim 1,wherein: A is selected from the group consisting of: (a) C₁-C₆-alkyl;(b) C₃-C₈-cycloalkyl; (c) phenyl, which is independently substitutedwith 0-2 R¹ substituents; (d) naphthyl, which is independentlysubstituted with 0-2 R¹ substituents; and (e) a monocyclic or fusedbicyclic heterocyclic ring system having from 5 to 10 ring atoms,wherein 1-4 ring atoms of the ring system are selected from the groupconsisting of N, O and S, and wherein the ring system may be substitutedwith 0-2 R¹ substituents; R¹ is selected from the group consisting of:halo, C₁₋₄alkyl, —CN, —NO₂, (CH₂)_(m)NR²R³, SO₂NR²R³, SO₂R², CF₃, OR²,and 5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O and S; R² and R³are independently selected from the group consisting of: H, C₁₋₄alkyl,C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl; m is an integer of 0-2; B is amember selected from the group consisting of: a direct link, —C(═O)—,—N(R⁴)—, —C(═O)—N(R⁴)—, —N(R⁴)—C(═O)—, —SO₂—, —O—, —SO₂—N(R⁴)— and—N(R⁴)—SO₂—; R⁴ is selected from the group consisting of: H, C₁₋₄alkyl,C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl; D is phenyl, which isindependently substituted with 0-2 R^(1a) substituents; R^(1a) isselected from the group consisting of: halo, C₁₋₄alkyl, —CN, —NO₂,(CH₂)_(m)NR^(2a)R^(3a), —SO₂NR^(2a)R^(3a), —SO₂R^(2a), CF₃, —OR^(2a),and a 5-6 membered aromatic heterocyclic system containing from 1-4heteroatoms selected from the group consisting of N, O and S; R^(2a) andR^(3a) are independently selected from the group consisting of: H,C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl; M, D and Ncollectively form a bicyclic ring structure selected from the groupconsisting of:

 wherein 0 to 2 of the hydrogen atoms on the D portion of the bicyclicring may be replaced by R^(1a) substituents as defined above; R¹⁷,R^(17a), R^(18a) and R^(18a) are each independently selected from thegroup consisting of: halo, C₁₋₄alkyl, —CN, —NO₂, (CH₂)_(m)NR²R³,SO₂NR²R³, SO₂R², CF₃, OR², and a 5-6 membered aromatic heterocyclicsystem containing from 1-4 heteroatoms selected from the groupconsisting of N, O and S; R^(17b) and R^(17c) are each independently amember selected from the group consisting of: hydrogen, -halo, hydroxy,—C₁₋₄alkyl, —CN, —NO₂, —(CH₂)_(m)NR²R³, —SO₂NR²R³, —SO₂R², —CF₃, —OR²,phenyl, and a 5-6 membered aromatic heterocyclic ring containing from1-4 heteroatoms selected from the group consisting of N, O and S; m isan integer from 0-6; E is a member selected from the group consistingof: a direct link, —C(═O)—, —C(═O)—N(R⁵)—, —C(—R^(5a),—R^(6a))— and—(—C(—R^(5b),—R^(6b))—C(—R^(5c),—R^(6c))—; wherein R⁵, R^(5a), R^(6a),R^(5b) R^(6b), R^(5c) and R^(6c) are independently selected from thegroup consisting of: H, C₁₋₄alkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl,C₀₋₄alkylheteroaryl, C₁₋₄alkylCOOH and C₁₋₄alkylCOOC₁₋₄alkyl, whereinfrom 0-2 hydrogen atoms on the ring atoms of the phenyl, naphthyl andheteroaryl moieties may be independently replaced with a member selectedfrom the group consisting of halo, C₁₋₄alkyl, —OH, —O—C,₄alkyl, —SH,—S—C₁₋₄alkyl, —CN and —NO₂; G is selected from the group consisting of:a direct link, —C(R⁷,R⁸)—, —C(R^(7a),R^(8a))—C (R^(7b),R^(8b))— and—C(R^(7c))═C(R^(8c))—; wherein R⁷, R⁸, R^(7a), R^(8a), R^(7b), R^(8b),R^(7c) and R^(8c) are independently a member selected from the groupconsisting of: hydrogen, halogen, C₁₋₄alkyl, C₀₋₄alkyl-C₃₋₈cycloalkyl,C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, —OR⁹, —N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹,—C₀₋₄alkylC(═O)NR⁹R¹⁰, —C₀₋₄alkylC(═O)NR⁹—CH₂—CH₂—O—R¹⁰,—C₀₋₄alkylC(═O)NR⁹(—CH₂—CH₂—O—R¹⁰—)₂, —N(R⁹)COR¹⁰, —N(R⁹)C(═O)R¹⁰,—N(R⁹)SO₂R¹⁰, and a naturally occurring or synthetic amino acid side chain; R⁹and R¹⁰ are independently selected from the group consisting of: H,C₁₋₄alkyl, C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl; J is a member selectedfrom the group consisting of: a direct link, —O—, —O—C(—R¹¹, —R^(11a))—,—S—, —S(═O)₂—, —S—C(—R¹¹, —R^(11a))—, —S(═O)₂—(—R¹¹,—R^(11a))—,—C(═O)—N(R^(11b))—,—N(R^(11b))—,—N(R^(11b))—C(—R¹¹,—R^(11a))— and a monocyclic aromatic ornon-aromatic heterocyclic ring having from 5 to 8 ring atoms, wherein1-4 ring atoms of the ring system are selected from the group consistingof N, O and S, and wherein the ring system may be substituted with 0-2R^(11c) substituents; R¹¹, R^(11a), R^(11b) and R^(11c) are a memberindependently selected from the group consisting of: hydrogen, halo,—CN, —NO₂, —OH, —O—C₁₋₄alkyl, —O—C₃₋₈cycloalkyl, —COOH,—C(═O)—O—C₁₋₄alkyl, —C(═O)—O—C₃₋₈cycloalkyl, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₀₋₄alkyl-C₃₋₈cycloalkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, and aC₀₋₄alkylheterocyclic ring having from 1 to 4 hetero ring atoms selectedfrom the group consisting of N, O and S, CH₂COOC₁₋₄alkyl,CH₂COOC₁₋₄alkylphenyl and CH₂COOC₁₋₄alkylnaphthyl; Y is a memberselected from the group consisting of: (a) phenyl, which isindependently substituted with 0-2 R^(1b) substituents; (b) naphthyl,which is independently substituted with 0-2 R^(1b) substituents; and (c)a monocyclic or fused bicyclic heterocyclic ring system having from 5 to10 ring atoms, wherein 1-4 ring atoms of the ring system are selectedfrom the group consisting of N, O and S, and wherein the ring system maybe substituted with 0-2 R^(1b) substituents; R^(1b) is a member selectedfrom the group consisting of: halo, C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, —NO₂, NR_(2b)R^(3b),SO₂NR_(2b)R^(3b), SO₂R^(2b), CF₃, OR^(2b), O—CH₂—CH₂—OR^(2b),O—CH₂—COOR^(2b), N(R^(2b))—CH₂—CH₂—OR^(2b), N(—CH₂—CH₂—OR^(2b))₂,N(R^(2b))—C(═O)R^(3b), N(R^(2b))—SO₂—R^(3b), and a 5-6 membered aromaticheterocyclic system containing from 1-4 heteroatoms selected from thegroup consisting of N, O and S, wherein from 1-4 hydrogen atoms on thearomatic heterocyclic system may be independently replaced with a memberselected from the group consisting of halo, C₁₋₄alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN and —NO₂;R^(2b) and R^(3b) are independently selected from the group consistingof: H, C₁₋₄alkyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl,C₀₋₄alkylphenyl and C₀₋₄alkylnaphthyl; L is selected from the groupconsisting of: H, —CN, C(═O)NR¹²R¹³,(CH₂)_(n)NR¹²R¹³, C(═NR¹²)NR¹²R¹³,OR¹², —NR¹²C(═NR¹²)NR¹²R¹³, and NR¹²C(═NR¹²)—R¹³; n is an integer from 0to 6; R¹² and R¹³ are independently selected from the group consistingof: hydrogen, —OR¹⁴, —NR¹⁴R¹⁵, C₁₋₄alkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, COOC₁₋₄alkyl, COO—C₀₋₄alkylphenyl andCOO—C₀₋₄alkylnaphthyl, wherein from 0-4 hydrogen atoms on the ring atomsof the phenyl and naphthyl moieties may be independently replaced with amember selected from the group consisting of halo, —OH, —O—C₁₋₄alkyl,C₁₋₄alkyl, C₃₋₈cycloalkyl, C₀₋₄alkylC₃₋₈cycloalkyl, —CN, and —NO₂; R¹⁴and R¹⁵ are independently selected from the group consisting of: H,C₁₋₄alkyl, C₀₋₄alkylC₃₋₈cycloalkyl, C₀₋₄alkylphenyl andC₀₋₄alkylnaphthyl; and all pharmaceutically acceptable isomers, salts,hydrates, solvates and prodrug derivatives thereof.
 12. A pharmaceuticalcomposition for preventing or treating a condition in a mammal havingundesired thrombosis comprising a therapeutically acceptable carrier anda therapeutically effective amount of a compound of claim
 11. 13. Amethod for preventing or treating a condition in a mammal havingundesired thrombosis comprising administering to said mammal atherapeutically effective amount of a compound of claim
 11. 14. Themethod of claim 13, wherein the condition is selected from the groupconsisting of: acute coronary syndrome, myocardial infarction, unstableangina, refractory angina, occlusive coronary thrombus occurringpost-thrombolytic therapy or post-coronary angioplasty, a thromboticallymediated cerebrovascular syndrome, embolic stroke, thrombolic stroke,transient ischemic attacks, venous thrombosis, deep venous thrombosis,pulmonary embolus, coagulopathy, disseminated intravascular coagulation,thrombotic thrombocytopenic purpura, thromboangiitis obliterans,thrombotic disease associated with heparin-induced thrombocytopenia,thrombotic complications associated with extracorporeal circulation,thrombotic complications associated with instrumentation such as cardiacor other intravascular catheterization, intra-aortic balloon pump,coronary stent or cardiac valve, and conditions requiring the fitting ofprosthetic devices.
 15. A method for inhibiting the coagulation ofbiological samples, comprising the administration of a compound of claim11.
 16. A compound of claim 1, wherein: A is selected from the groupconsisting of: (a) phenyl, which is independently substituted with 0-2R¹ substituents; and (b) a monocyclic or fused bicyclic heterocyclicring system having from 5 to 10 ring atoms, wherein 1-4 ring atoms ofthe ring system are selected from the group consisting of N, O and S,and wherein the ring system may be substituted with 0-2 R¹ substituents;R¹ is selected from the group consisting of: halo, (CH₂)_(m)NR²R³,SO₂NR²R³ and SO₂R²; R² and R³ are independently selected from the groupconsisting of: H and C₁₋₄alkyl; m is an integer of 0-2; Q is a memberselected from the group consisting of: a direct link, —C(═O)—, —SO₂—,and —O—; D is phenyl, which is independently substituted with 0-2 R^(1a)substituents; R^(1a) is selected from the group consisting of: halo andC₁₋₄alkyl; M, D and N collectively form a bicyclic ring structureselected from the group consisting of:

 R¹⁷, R^(17a), R¹⁸ and R^(18a) are each independently selected from thegroup consisting of: halo, C₁₋₄alkyl, —CN, —NO₂, (CH₂)_(m)NR²R³,SO₂NR²R³, SO₂R², CF₃ and OR²; R^(17b) and R^(17c) are each independentlya member selected from the group consisting of: hydrogen, -halo,hydroxy, —C₁₋₄alkyl, —CN, —NO₂, —(CH₂)_(m)NR²R³, —SO₂NR²R³, —SO₂R²,—CF₃, —OR², phenyl, and a 5-6 membered aromatic heterocyclic ringcontaining from 1-3 N atoms; E is a member selected from the groupconsisting of: a direct link, —C(═O)—, —C(═O)—N(R⁵)—,—C(—R^(5a),—R^(6a))— and —(—C(—R^(5a),—R^(6a))—C(—R^(5c),—R^(6c))—;wherein R⁵, R^(5a), R^(6a), R^(5b) R^(6b), R^(5c) and R^(6c) areindependently selected from the group consisting of: H, C₁₋₄alkyl,C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, C₀₋₄alkylheteroaryl, C₁₋₄alkylCOOHand C₁₋₄alkylCOOC₁₋₄alkyl; G is selected from the group consisting of: adirect link, —C(R⁷,R⁸)—, —C(R^(7a)R^(8a))—C(R^(7b),R^(8b))— and—C(R^(7c))═C(R^(8c))—; wherein R⁷, R⁸, R^(7a), R^(8a), R^(7b), R^(8b),R^(7c) and R^(8c) are independently a member selected from groupconsisting of: hydrogen, halogen, C₁₋₄alkyl, C₀₋₄alkyl-C₃₋₈cycloalkyl,C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl, —OR⁹, —N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹,—C₀₋₄alkylC(═O)NR⁹R¹⁰, —C₀₋₄alkylC(═O)NR⁹—CH₂—CH₂—O—R¹⁰,—C₀₋₄alkylC(═O)NR⁹(—CH₂—CH₂—O—R^(10—)) ₂, —N(R⁹)COR¹⁰,—N(R⁹)C(═O)R¹⁰,—N(R⁹) SO₂R¹⁰, and a naturally occurring or syntheticamino acid side chain; R⁹ and R¹⁰ are independently selected from thegroup consisting of: H, C₁₋₄alkyl, C₀₋₄alkylphenyl andC₀₋₄alkylnaphthyl; J is a member selected from the group consisting of:a direct link, —O—, —S—, —C(═O)—N(R^(11b))—, —N(R^(11b))—,—N(R^(11b))—C(—R¹¹, —R^(11a))— and a monocyclic aromatic or non-aromaticheterocyclic ring having from 5 to 8 ring atoms, wherein 1-4 ring atomsof the ring system are selected from the group consisting of N, O and S,and wherein the ring system may be substituted with 0-2 R^(11c)substituents; R¹¹, R^(11a), R^(11b) and R^(11c) are a memberindependently selected from the group consisting of: hydrogen, halo,—CN, —NO₂, —OH, —O—C₁₋₄alkyl, —O—C₃₋₈cycloalkyl, —COOH,—C(═O)—O—C₁₋₄alkyl, —C(═O)—O—C₃₋₈cycloalkyl, C₁₋₄alkyl, C₃₋₈cycloalkyl,C₀₋₄alkyl—C₃₋₈cycloalkyl, C₁₋₄alkylphenyl, C₀₋₄alkylnaphthyl, and aC₀₋₄alkylheterocyclic ring having from 1 to 4 hetero ring atoms selectedfrom the group consisting of N, O and S, CH₂COOC₁₋₄alkyl,CH₂COOC₁₋₄alkylphenyl and CH₂COOC₁₋₄alkylnaphthyl; Y is a memberselected from the group consisting of: (a) phenyl, which isindependently substituted with 0-2 R^(1b) substituents; (b) an aromaticheterocyclic ring having from 5 to 10 ring atoms, wherein 1-4 ring atomsof the ring system are selected from the group consisting of N, O and S,and wherein the ring may be substituted with 0-2 R^(1b) substituents;(c) a fused aromatic bicyclic heterocyclic ring system having from 5 to10 ring atoms, wherein 1-4 ring atoms of the ring system are selectedfrom the group consisting of N, O and S, and wherein the bicyclic ringsystem may be substituted with 0-2 R^(1b) substituents; R^(1b) is amember selected from the group consisting of: halo, —C₁₋₄alkyl, —OH,—OBn, —O—CH₂—CH₂—OH, —O—CH₂—CH₂—OCH₃, —O—CH₂—COOH, —O—CH₂—C(═O)—O—CH₃,—NH₂, —NH—CH₂—CH₂—O—CH₃, —NH—C(═O)—O—CH₃ and —NH—SO₂—CH₃; L is selectedfrom the group consisting of: H, —C(═O)NR¹²R¹³, —(CH₂)_(n)NR¹²R¹³ and—C(═NR¹²)N¹²R¹³; n is an integer from 0 to 6; R¹² and R¹³ areindependently selected from the group consisting of: hydrogen andC₁₋₄alkyl; and all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives thereof.
 17. A pharmaceuticalcomposition for preventing or treating a condition in a mammal havingundesired thrombosis comprising a therapeutically acceptable carrier anda therapeutically effective amount of a compound of claim
 16. 18. Amethod for preventing or treating a condition in a mammal havingundesired thrombosis comprising administering to said mammal atherapeutically effective amount of a compound of claim
 16. 19. Themethod of claim 18, wherein the condition is selected from the groupconsisting of: acute coronary syndrome, myocardial infarction, unstableangina, refractory angina, occlusive coronary thrombus occurringpost-thrombolytic therapy or post-coronary angioplasty, a thromboticallymediated cerebrovascular syndrome, embolic stroke, thrombotic stroke,transient ischemic attacks, venous thrombosis, deep venous thrombosis,pulmonary embolus, coagulopathy, disseminated intravascular coagulation,thrombotic thrombocytopenic purpura, thromboangiitis obliterans,thrombotic disease associated with heparin-induced thrombocytopenia,thrombotic complications associated with extracorporeal circulation,thrombotic complications associated with instrumentation such as cardiacor other intravascular catheterization, intra-aortic balloon pump,coronary stent or cardiac valve, and conditions requiring the fitting ofprosthetic devices.
 20. A method for inhibiting the coagulation ofbiological samples, comprising the administration of a compound of claim16.
 21. A compound of claim 1, wherein A is a member selected from thegroup consisting of:

Q is a member selected from the group consisting of:

E is a member selected from the group consisting of: a direct link,—C(═O)—, —C(═O)—N(R⁵)—, —C(R^(5a),—R^(6a))— and—(—C(—R^(5a),—R^(6a))—C(—R^(5c),—R^(6c))—; wherein R⁵, R^(5a), R^(6a),R^(5b) R^(6b), R^(5c) and R^(6c) are independently selected from thegroup consisting of: H, C₁₋₄alkyl, C₀₋₄alkylphenyl, C₀₋₄alkylnaphthyl,C₀₋₄alkylheteroaryl, C₁₋₄alkylCOOH and C₁₋₄alkylCOOC₁₋₄alkyl; G isselected from the group consisting of: a direct link, —C(R⁷,R⁸)—,—C(R^(7a),R^(8a))—C(R^(7b),R^(8b))— and —C(R^(7c))═C(R^(8c))—; whereinR⁷, R⁸, R^(7a), R^(8a), R^(7b), R^(8b), R^(7c) and R^(8c) areindependently a member selected from the group consisting of: hydrogen,halogen, C₁₋₄alkyl, C₀₋₄alkyl-C₃₋₈cycloalkyl, C₀₋₄alkylphenyl,C₀₋₄alkylnaphthyl, —OR⁹, —N(R⁹R¹⁰), —C₀₋₄alkylCOOR⁹,—C₀₋₄alkylC(═O)NR⁹R¹⁰, —C₀₋₄alkylC(═O)NR⁹—CH₂—CH₂—O—R¹⁰,—C₀₋₄alkylC(═O)NR⁹(—CH₂—CH₂—O—R¹⁰—)₂, —N(R⁹)COR¹⁰,—N(R⁹)C(═O)R¹⁰,—N(R⁹)SO₂R¹⁰, and a naturally occurring or syntheticamino acid side chain; R⁹ and R¹⁰ are independently selected from thegroup consisting of: H, C₁₋₄alkyl, C₀₋₄alkylphenyl andC₀₋₄alkylnaphthyl; J is a member selected from the group consisting of:a direct link, —O—, —S—, —C(═O)—N(R^(11b))—, —N(R^(11b))—,—N(R^(11b))—C(—R¹¹, —R^(11a))— and a monocyclic aromatic or non-aromaticheterocyclic ring having from 5 to 8 ring atoms, wherein 1-4 ring atomsof the ring system are selected from the group consisting of N, O and S,and wherein the ring system may be substituted with 0-2 R^(11c)substituents; R¹¹, R^(11a), R^(11b) and R^(11c) are a memberindependently selected from the group consisting of: hydrogen, halo,—CN, —NO₂, —OH, —O—C₁₋₄alkyl, —C₁₋₄alkyl, —COOH, phenyl, and benzylwherein the aromatic ring of the phenyl or benzyl is substituted with0-2 members independently selected from the group consisting of halo,—CN, —NO₂, —OH, —O—C₁₋₄alkyl, —C₁₋₄alkyl, —COOH and —C(═O)—O—C₁₋₄alkyl;Y and L taken together are a member selected from the group consistingof:

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.
 22. A pharmaceutical composition forpreventing or treating a condition in a mammal having undesiredthrombosis comprising a therapeutically acceptable carrier and atherapeutically effective amount of a compound of claim
 21. 23. A methodfor preventing or treating a condition in a mammal having undesiredthrombosis comprising administering to said mammal a therapeuticallyeffective amount of a compound of claim
 21. 24. The method of claim 23,wherein the condition is selected from the group consisting of: acutecoronary syndrome, myocardial infarction, unstable angina, refractoryangina, occlusive coronary thrombus occurring post-thrombolytic therapyor post-coronary angioplasty, a thrombotically mediated cerebrovascularsyndrome, embolic stroke, thrombotic stroke, transient ischemic attacks,venous thrombosis, deep venous thrombosis, pulmonary embolus,coagulopathy, disseminated intravascular coagulation, thromboticthrombocytopenic purpura, thromboangiitis obliterans, thrombotic diseaseassociated with heparin-induced thrombocytopenia, thromboticcomplications associated with extracorporeal circulation, thromboticcomplications associated with instrumentation such as cardiac or otherintravascular catheterization, intra-aortic balloon pump, coronary stentor cardiac valve, and conditions requiring the fitting of prostheticdevices.
 25. A method for inhibiting the coagulation of biologicalsamples, comprising the administration of a compound of claim
 21. 26. Acompound of claim 1, having the formula:

wherein the following portion of said formula

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(11b) is selected from the group consisting of: H, Me, Ph,OMe, F, OH, Br, NH₂, OCH₂Ph, OCH₂CH₂OMe,

and wherein R⁷ is selected from the group consisting of: H; Me; Et; Ph;


27. A compound of claim 1, having the formula:

wherein the following portion of said formula

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(11c1) is selected from the group consisting of: H; Me; Et;Ph; OMe; CF₃, F; OH; Br; NH₂; SO₂Me; OCH₂Ph; OCH₂CH₂OMe;

 and wherein R^(11c2) is selected from the group consisting of: H; Me;Et; Cl; Br; F; Ph;


28. A compound of claim 1, having the formula:

wherein the following portion of said formula

 is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(11c1) selected from the group consisting of: H, Me, Ph, OMe,F, OH, Br, NH₂, OCH₂Ph, OCH₂CH₂OMe,

and wherein R^(11c2) is selected from the group consisting of: H; Me;Et; Ph;


29. A compound of claim 1, having the formula:

wherein the following portion of said formula:

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(11c1) is selected from the group consisting of: H, Me, Ph,OMe, F, OH, Br, NH₂, OCH₂Ph, OCH₂CH₂OMe,

and wherein R^(11c2) is selected from the group consisting of: H; Me;Et; Ph;


30. A compound of claim 1, having the formula:

wherein the following portion of said formula

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(7c) is selected from the group consisting of: H, Me, Ph, OMe,F, OH, Br, NH₂, OCH₂Ph, OCH₂CH₂OMe,

and wherein R^(8c) is selected from the group consisting of: H; Me; Et;Ph;


31. A compound of claim 1, having the formula:

wherein the following portion of said formula

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(7a) is selected from the group consisting of: H, Me, Ph, OMe,F, OH, Br, NH₂OCH₂Ph, OCH₂CH₂OMe,

and wherein R^(7b) is selected from the group consisting of: H; Me; Et;Ph;


32. A compound of claim 1, having the formula:

wherein the following portion of said formula

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(7a) is selected from the group consisting of: H, Me, Ph, OMe,F, OH, Br, NH₂, OCH₂Ph, OCH₂CH₂OMe,

and wherein R^(7b) is selected from the group consisting of: H; Me; Et;Ph;


33. A compound of claim 1, having the formula:

wherein the following portion of said formula

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(6c) is selected from the group consisting of: H, Me Et; Ph;OMe; F; OH; Br; NH₂; SO₂Me; OCH₂Ph; OCH₂CH₂OMe;

and wherein R^(11b) is selected from the group consisting of: H; Me; Et;Cl; Br; F; Ph;


34. A compound of claim 1, having the formula:

wherein the following portion of said formula

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(11c1) is selected from the group consisting of: H; Me; Et;Ph; OMe; F; OH; Br; NH₂; SO₂Me; OCH₂Ph; OCH₂CH₂OMe;

and wherein R^(11c2) is selected from the group consisting of: H; Me;Et; Cl; Br; F; Ph;


35. A compound of claim 1, having the formula:

wherein the following portion of said formula

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(11c1) is selected from the group consisting of: H; Me; Et;Ph; OMe; F; OH; Br; NH₂; SO₂Me; OCH₂Ph; OCH₂CH₂OMe;

and wherein R^(11c2) is selected from the group consisting of: H; Me;Et; Cl; Br; F; Ph;


36. A compound of claim 1, having the formula:

wherein the following portion of said formula

is selected from the group consisting of:

wherein Y and L, taken together, are selected from the group consistingof:

wherein R^(11c1) is selected from the group consisting of: H; Me; Et;Ph; OMe; F; OH; Br; NH₂; SO₂Me; OCH₂Ph; OCH₂CH₂OMe;

and wherein R^(11c2) is selected from the group consisting of: H; Me;Et; Cl; Br; F; Ph;


37. A compound of claim 1, selected from the group consisting of:


38. A compound according to the formula:

wherein A—Q— is selected from the group consisting of: t-Bu; O-t-Bu;—(CH₂)₀₋₅-amino; OH; carboxylic acid ester; carboxamide;


39. A compound of claim 1, selected from the group consisting of:


40. A compound of claim 1, selected from the group consisting of:


41. A compound of claim 1, selected from the group consisting of:


42. A compound, selected from the group consisting of:

wherein Q is a direct link, and A is a member selected from the group:

or Q is a —C(═NH)— group, and A is a member selected from the group:

G is a direct link; J is a member selected from the group:

Y—L is a member selected from the group: